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  • 1.
    Basic, Vladimir T.
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Jacobsen, Annette
    Charles Sturt University, Sydney NSW, Australien.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Abdel-Halim, Samy
    Danderyd Hospital, Stockholm, Sweden.
    TNF stimulation induces VHL overexpression and impairs angiogenic potential in skeletal muscle myocytes2014In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 34, no 1, p. 228-236Article in journal (Refereed)
    Abstract [en]

    Decreased skeletal muscle capillarization is considered to significantly contribute to the development of pulmonary cachexia syndrome (PCS) and progressive muscle wasting in several chronic inflammatory diseases, including chronic obstructive pulmonary disease (COPD). It is unclear to which extent the concurrent presence of systemic inflammation contributes to decreased skeletal muscle capillarization under these conditions. The present study was designed to examine in vitro the effects of the pro-inflammatory cytokine, tumor necrosis factor (TNF), on the regulation of hypoxia-angiogenesis signal transduction and capillarization in skeletal muscles. For this purpose, fully differentiated C2C12 skeletal muscle myocytes were stimulated with TNF and maintained under normoxic or hypoxic conditions. The expression levels of the putative elements of the hypoxia-angiogenesis signaling cascade were examined using qPCR, western blot analysis and immunofluorescence. Under normoxic conditinos, TNF stimulation increased the protein expression of anti-angiogenic von-Hippel Lindau (VHL), prolyl hydroxylase (PHD)2 and ubiquitin conjugating enzyme 2D1 (Ube2D1), as well as the total ubiquitin content in the skeletal muscle myocytes. By contrast, the expression levels of hypoxia-inducible factor 1‑α (HIF1-α) and those of its transcriptional targets, vascular endothelial growth factor (VEGF)A and glucose transporter 1 (Glut1), were markedly reduced. In addition, hypoxia increased the expression of the VHL transcript and further elevated the VHL protein expression levels in C2C12 myocytes following TNF stimulation. Consequently, an impaired angiogenic potential was observed in the TNF-stimulated myocytes during hypoxia. In conclusion, TNF increases VHL expression and disturbs hypoxia-angiogenesis signal transduction in skeletal muscle myocytes. The current findings provide a mechanism linking systemic inflammation and impaired angiogenesis in skeletal muscle. This is particularly relevant to further understanding the mechanisms mediating muscle wasting and cachexia in patients with chronic inflammatory diseases, such as COPD.

  • 2.
    Basic, Vladimir T.
    et al.
    Department of Clinical Medicine, Örebro University, Örebro, Sweden.
    Jacobsen, Annette
    Department of Clinical Medicine, Örebro University, Örebro, Sweden; School of Biomedical Sciences, Charles Sturt University, WaggaWagga, Australia.
    Tadele, Elsa
    Department of Clinical Medicine, Örebro University, Örebro, Sweden; Medical University of Giessen, Molecular Biology and Medicine of the Lung program, Giessen, Germany.
    Banjop- Kharlyngdoh, Joubert
    Örebro University, School of Science and Technology.
    Sirsjö, Allan
    Department of Clinical Medicine, Örebro University, Örebro, Sweden.
    Abdel-Halim, Samy M.
    Division of Respiratory Medicine and Allergology, Department of Clinical Sciences, Danderyd Hospital, Stockholm, Sweden.
    Cigarette smoke exposure up-regulates Ubiquitin specific protease 19 in murine skeletal muscles as an adaptive response to prolonged ER stressManuscript (preprint) (Other academic)
    Abstract [en]

    Enhanced protein degradation via ubiquitin proteolytic system (UPS) was demonstrated to play an important role in the pathogenesis of cachexia syndrome and muscle wasting in patients with COPD and animal models of the disease. The role of cigarette smoke (CS) exposure in eliciting these abnormalities remains largely unknown. Usp19 is a member of UPS suggested to be involved in progressive muscle wasting in different catabolic conditions. However, factors regulating Usp19 expression, activity and correlation/s with CS-induced muscle atrophy remainunclear.

    Methods: To address these questions, 129 SvJ mice were exposed to cigarette smoke for 6 months and the gastrocnemius muscles were collected. Expression levels of Usp19 as well as pivotal mediators of ER stress response have been studied using PCR, qPCR, western blot and immunofluorescence. Factors regulating muscle Usp19 expression were studied using in-silico analysis of Usp19 promoter as well as by stimulating C2C12 myocytes with different inducers of ER stress including hypoxia, TNF and tunicamycin. Finally, Usp19 expression was depleted in C2C12 myocytes using specific Usp19 siRNA quadriplex and the expression of pivotal myogenic regulators were analyzed.

    Results: Usp19 mRNA expression was enhanced in skeletal muscles of CS-exposed mice. Concurrently, ER stress-associated Caspase 12 and Caspase 3 were activated in the CS-exposed group. Analysis of Usp19 promoter sequence revealed binding sites for ER stress response transcription factors such as HSF, STRE1 and AML1-α. Exposure of C2C12 myocytes to tunicamycin but not hypoxia elevated expression levels of Usp19. TNFstimulation elevated Usp19 protein expression but inhibited its RNA transcription in a dose- and time-dependent manner. Finally, Usp19 overexpression in tunicamycin-treated myocytes was accompanied by reduced expression of myosin heavy chain and tropomyosin and their levels were increased after knocking down Usp19 in C2C12 myocytes.

    Conclusions: In summary, our data demonstrated elevated expression of Usp19 in skeletal muscles of CS-exposed 129 SvJ mice. Moreover, Usp19 overexpression was associated with muscle adaptations to ER stress and suppression of myogenesis. Taken together; our results might provide further insight into molecular mechanisms underlying development and progression of skeletal muscle abnormalities in response to chronic cigarette smoke exposure.

  • 3.
    Basic, Vladimir T.
    et al.
    Department of Clinical Medicine, Örebro University, Örebro, Sweden.
    Tadele, Elsa
    Department of Clinical Medicine, Örebro University, Örebro, Sweden; Medical University of Giessen, Molecular Biology and Medicine of the Lung program, Giessen, Germany.
    Jacobsen, Annette
    Department of Clinical Medicine, Örebro University, Örebro, Sweden; School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, Australia.
    Sirsjö, Allan
    Department of Clinical Medicine, Örebro University, Örebro, Sweden.
    Abdel-Halim, Samy M.
    Division of Respiratory Medicine and Allergology, Department of Clinical Sciences, Danderyd Hospital, Stockholm, Sweden.
    Chronic cigarette smoke exposureimpairs skeletal muscle regenerative capacity in murineCOPD/emphysema model.Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Cigarette smoke (CS) is a well established risk factor in the development of COPD and irreversible airflow limitation. In contrast, the extent to which CS exposure contributes to development of peripheral skeletal muscle dysfunction and wasting remains largely unknown. Decline in skeletal muscle regenerative capacity has been previously reported in COPD patients.

    Methods: To investigate effects of chronic CS exposure on skeletal muscle regenerative capacity, 129/SvJ mice were exposed to CS for 6 months. The expression levels of myogenin, Jarid2, Znf496, Notch1, Pax7, Fgf1 and Myh3, which are known to regulate skeletal muscle myogenesis, were studied. Additionally, number of fibers with central nuclei, myonuclei number and mean fiber cross-sectional area were assessed.

    Results: Compared to controls, skeletal muscles from CS-exposed mice exhibited significantly decreased expression of Jarid2, coupled with enhanced expression of Znf496, Notch1, Pax7, Fgf1 and Myh3. Expression of myogenin, a marker of terminally differentiated myofibers, was reduced. Furthermore, reduced muscle fiber crosssectional area, increased number of fibers with central nuclei and reduced myonuclei number were also observed in CS-exposed animals.

    Conclusions: Taken together, current results provide evidence linking chronic CS exposure and an ongoing damage/repair process as well as impaired regenerative capacity in skeletal muscles of CS-exposed mice.

  • 4.
    Basic, Vladimir Tomislav
    et al.
    Department of Clinical Medicine, Örebro University, Örebro, Sweden.
    Tadele, Elsa
    Department of Clinical Medicine, Örebro University, Örebro, Sweden.
    Elmabsout, Ali Ateia
    Department of Clinical Medicine, Örebro University, Örebro, Sweden.
    Yao, Hongwei
    Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Rochester NY, USA.
    Rahman, Irfan
    Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Rochester NY, USA.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Abdel-Halim, Samy M.
    Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Rochester NY, USA.
    Exposure to cigarette smoke induces overexpression of von Hippel-Lindau tumor suppressor in mouse skeletal muscle2012In: American Journal of Physiology - Lung cellular and Molecular Physiology, ISSN 1040-0605, E-ISSN 1522-1504, Vol. 303, no 6, p. L519-L527Article in journal (Refereed)
    Abstract [en]

    Cigarette smoke (CS) is a well established risk factor in the development of chronic obstructive pulmonary disease (COPD). In contrast, the extent to which CS exposure contributes to the development of the systemic manifestations of COPD, such as skeletal muscle dysfunction and wasting remains largely unknown. Decreased skeletal muscle capillarization has been previously reported in early stages of COPD and might play an important role in the development of COPD-associated skeletal muscle abnormalities. To investigate the effects of chronic CS exposure on skeletal muscle capillarization and exercise tolerance a mouse model of CS exposure was used. The129/SvJ mice were exposed to CS for 6 months, and the expression of putative elements of the hypoxia-angiogenic signaling cascade as well as muscle capillarization were studied. Additionally, functional tests assessing exercise tolerance/endurance were performed in mice. Compared to controls, skeletal muscles from CS-exposed mice exhibited significantly enhanced expression of von Hippel-Lindau tumor suppressor (VHL), ubiquitin-conjugating enzyme E2D1 (UBE2D1) and prolyl hydroxylase-2 (PHD2). In contrast, hypoxia-inducible factor-1 (HIF1-α) and vascular endothelial growth factor (VEGF) expression was reduced. Furthermore, reduced muscle fiber cross-sectional area, decreased skeletal muscle capillarization, and reduced exercise tolerance were also observed in CS-exposed animals. Taken together, the current results provide evidence linking chronic CS exposure and induction of VHL expression in skeletal muscles leading towards impaired hypoxia-angiogenesis signal transduction, reduced muscle fiber cross-sectional area and decreased exercise tolerance.

  • 5.
    Bilbija, Dusan
    et al.
    University of Oslo, Oslo, Norway.
    Elmabsout, Ali Ateia
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Sagave, Julia
    University of Oslo, Oslo, Norway.
    Haugen, Fred
    University of Oslo, Oslo, Norway.
    Bastani, Nasser
    Departments of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
    Dahl, Christen Peder
    University of Oslo, Oslo, Norway; Department of Cardiology, Oslo University Hospital, Oslo, Norway .
    Gullestad, Lars
    University of Oslo, Oslo, Norway; Department of Cardiology, Oslo University Hospital, Oslo, Norway.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Blomhoff, Rune
    Departments of Nutrition, Institute of Basic Medical Sciences, Oslo University, Oslo, Norway.
    Valen, Guro
    University of Oslo, Oslo, Norway.
    Expression of retinoic acid target genes in coronary artery disease2014In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 33, no 3, p. 677-86Article in journal (Refereed)
    Abstract [en]

    Coronary atherosclerosis can lead to myocardial infarction, and secondarily to post-infarct remodelling and heart failure. Retinoic acid (RA) influences cell proliferation. We hypothesized that RA could influence gene expression and proliferation of cardiovascular cells. Left ventricular biopsies from patients with end-stage heart failure due to coronary artery disease (CAD) or dilated cardiomyopathy were investigated for the content of RA metabolites using liquid chromatography mass spectrometry (LC-MS/MS), and compared with healthy donors. All-trans retinoic acid (ATRA) was increased in the hearts of CAD patients. Gene expression (quantitative PCR) of RA target genes was not influenced in failing hearts, but was increased in the hearts of patients with CAD undergoing open heart surgery. The expression of RA target genes was increased in atherosclerotic lesions from carotid arteries compared to healthy arteries. Stimulation of cardiomyocytes, cardiofibroblasts, smooth muscle cells and endothelial cells with ATRA increased the gene expression of the key enzymes. Cardiofibroblast and smooth muscle cell proliferation were reduced by ATRA, which increased endothelial cell proliferation. Coronary artery disease leads to increased expression of RA target genes. ATRA accumulated in the failing human heart. All investigated cell types present in the heart had induced expression of RA target genes when stimulated with ATRA, which also influenced cell proliferation.

  • 6.
    Bilbija, Dusan
    et al.
    Department of Physiology, University of Oslo, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
    Haugen, Fred
    Department of Physiology, University of Oslo, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
    Sagave, Julia
    Department of Physiology, University of Oslo, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
    Baysa, Anton
    Department of Physiology, University of Oslo, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
    Bastani, Nasser
    Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway .
    Levy, Finn Olav
    Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Division of Biomedicine, Department of Clinical Medicine, School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Blomhoff, Rune
    Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway .
    Valen, Guro
    Department of Physiology, University of Oslo, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
    Retinoic acid signalling is activated in the postischemic heart and may influence remodelling2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 9, article id e44740Article in journal (Refereed)
    Abstract [en]

    Background: All-trans retinoic acid (atRA), an active derivative of vitamin A, regulates cell differentiation, proliferation and cardiac morphogenesis via transcriptional activation of retinoic acid receptors (RARs) acting on retinoic acid response elements (RARE).We hypothesized that the retinoic acid (RA) signalling pathway is activated in myocardial ischemia and postischemic remodelling.

    Methods and Findings: Myocardial infarction was induced through ligating the left coronary artery in mice. In vivo cardiac activation of the RARs was measured by imaging RARE-luciferase reporter mice, and analysing expression of RAR target genes and proteins by real time RT-PCR and western blot. Endogenous retinoids in postinfarcted hearts were analysed by triple-stage liquid chromatography/tandem mass spectrometry. Cardiomyocytes (CM) and cardiofibroblasts (CF) were isolated from infarcted and sham operated RARE luciferase reporter hearts and monitored for RAR activity and expression of target genes. The effect of atRA on CF proliferation was evaluated by EdU incorporation. Myocardial infarction increased thoracic RAR activity in vivo (p<0.001), which was ascribed to the heart through ex vivo imaging (p = 0.002) with the largest signal 1 week postinfarct. This was accompanied by increased cardiac gene and protein expression of the RAR target genes retinol binding protein 1 (p = 0.01 for RNA, p = 0,006 for protein) and aldehyde dehydrogenase 1A2 (p = 0.04 for RNA, p = 0,014 for protein), while gene expression of cytochrome P450 26B1 was downregulated (p = 0.007). Concomitantly, retinol accumulated in the infarcted zone (p = 0.02). CM and CF isolated from infarcted hearts had higher luminescence than those from sham operated hearts (p = 0.02 and p = 0.008). AtRA inhibited CF proliferation in vitro (p = 0.02).

    Conclusions: The RA signalling pathway is activated in postischemic hearts and may play a role in regulation of damage and repair during remodelling.

  • 7.
    El Marghani, Ahmed M.
    et al.
    Örebro University, School of Science and Technology.
    Abuabaid, Hanan M.
    Örebro University, School of Health and Medical Sciences.
    Hurtig-Wennlöf, Anita
    Örebro University, School of Health and Medical Sciences.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences.
    Norgren, Lars
    Department of Surgery, Örebro University Hospital, Örebro, Sweden.
    Kjellén, Peter
    Örebro University, School of Science and Technology.
    High MAPK p38 activity and low level of IL-10 in intermittent claudication as opposed to stable angina2010In: International Journal of Angiology, ISSN 0392-9590, E-ISSN 1827-1839, Vol. 29, no 4, p. 331-337Article in journal (Refereed)
    Abstract [en]

    AIM:

    The aim of the present pilot study was to relate the activity of MAPK p38 with the levels of pro- and anti-inflammatory cytokines in a small cohort of patients with either stable angina (N=5) or intermittent claudication (N=5) compared to healthy controls (N=10).

    METHODS:

    The activity of MAPK p38 was determined in peripheral blood mononuclear cells, isolated from whole blood by western blot using phospho-specific anti-MAPK p38 antibodies. Cytokine levels of 11 pro- and anti-inflammatory cytokines were determined from the serum using flow cytometry.

    RESULTS:

    We found a significant elevation of the MAPK p38 activity in the intermittent claudication group (P=0.0027) compared with the healthy control group whereas the stable angina group showed similar MAPK p38 activity as the healthy control group. The IL-10 level in serum found in the stable angina group was significantly higher compared with both the healthy control group (P=0.0116) and the intermittent claudication group (P=0.0317).

    CONCLUSION:

    Our results imply that there is a casual relationship between increased levels of the anti-inflammatory cytokines IL-10 and IL-4 and the activity of the MAPK p38. Possibly has IL-10 a protective role that down-regulates the activity of MAPK p38 and thereby further inflammatory processes in stable angina patients.

  • 8.
    Elmabsout, Ali Ateia
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fransén, Karin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Sundman, Eva
    Karikas, George
    Törmä, Hans
    Olofsson, Peder S.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Simvastatin and rosuvastatin inhibit CYP26B1-mediated retinoid catabolismManuscript (preprint) (Other academic)
  • 9.
    Elmabsout, Ali Ateia
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Kumawat, Ashok K.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Saenz-Méndez, Patricia
    Computational Chemistry and Biology Group, Facultad de Química, UdelaR, Montevideo, Uruguay.
    Krivospitskaya, Olesya
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Sävenstrand, Helena
    Örebro University, School of Science and Technology.
    Olofsson, Peder S.
    Department of Medicine, Karolinska Institutet, Center for Molecular Medicine, Stockholm, Sweden; Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset NY, United States of America.
    Eriksson, Leif A.
    Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg, Sweden.
    Strid, Åke
    Örebro University, School of Science and Technology.
    Valen, Guro
    Department of Physiology, Institute of Basic Medical Science and Center for Heart Failure Research, University of Oslo, Oslo, Norway.
    Törmä, Hans
    Department of Medical Sciences, Dermatology and Venereology, Uppsala University, Uppsala, Sweden.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Cloning and functional studies of a splice variant of CYP26B1 expressed in vascular cells2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 5, article id e36839Article in journal (Refereed)
    Abstract [en]

    Background: All-trans retinoic acid (atRA) plays an essential role in the regulation of gene expression, cell growth and differentiation and is also important for normal cardiovascular development but may in turn be involved in cardiovascular diseases, i.e. atherosclerosis and restenosis. The cellular atRA levels are under strict control involving several cytochromes P450 isoforms (CYPs). CYP26 may be the most important regulator of atRA catabolism in vascular cells. The present study describes the molecular cloning, characterization and function of atRA-induced expression of a spliced variant of the CYP26B1 gene.

    Methodology/Principal Findings: The coding region of the spliced CYP26B1 lacking exon 2 was amplified from cDNA synthesized from atRA-treated human aortic smooth muscle cells and sequenced. Both the spliced variant and full length CYP26B1 was found to be expressed in cultured human endothelial and smooth muscle cells, and in normal and atherosclerotic vessel. atRA induced both variants of CYP26B1 in cultured vascular cells. Furthermore, the levels of spliced mRNA transcript were 4.5 times higher in the atherosclerotic lesion compared to normal arteries and the expression in the lesions was increased 20-fold upon atRA treatment. The spliced CYP26B1 still has the capability to degrade atRA, but at an initial rate one-third that of the corresponding full length enzyme. Transfection of COS-1 and THP-1 cells with the CYP26B1 spliced variant indicated either an increase or a decrease in the catabolism of atRA, probably depending on the expression of other atRA catabolizing enzymes in the cells.

    Conclusions/Significance: Vascular cells express the spliced variant of CYP26B1 lacking exon 2 and it is also increased in atherosclerotic lesions. The spliced variant displays a slower and reduced degradation of atRA as compared to the fulllength enzyme. Further studies are needed, however, to clarify the substrate specificity and role of the CYP26B1 splice variant in health and disease.

  • 10.
    Elmabsout, Ali
    et al.
    Örebro University, School of Health and Medical Sciences.
    Kumawat, Ashok K.
    Örebro University, School of Health and Medical Sciences.
    Karlsson, Magnus
    Örebro University, School of Science and Technology.
    Krivospitskaya, Olesya
    Örebro University, School of Health and Medical Sciences.
    Sävenstrand, Helena
    Örebro University, School of Science and Technology.
    Hans, Törmä
    Uppsala universitet, Uppsala, Sweden.
    Strid, Åke
    Örebro University, School of Science and Technology.
    Eriksson, Leif A
    Örebro University, School of Science and Technology.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences.
    Cloning and functional studies of a splice variant of CYP26B1: a cellular storage protein for all-trans retinoic acid2010In: In Vivo, ISSN 0258-851X, E-ISSN 1791-7549, Vol. 24, no 3, p. 345-346Article in journal (Refereed)
    Abstract [en]

    Background

    All-trans retinoic acid (atRA) plays an essential role in the regulation of gene expression, cell growth and differentiation and is also important for normal cardiovascular development but may in turn be involved in cardiovascular diseases, i.e. atherosclerosis and restenosis. The cellular atRA levels are under strict control involving several cytochromes P450 isoforms (CYPs). CYP26 may be the most important regulator of atRA catabolism in vascular cells. The present study describes the molecular cloning, characterization and function of atRA-induced expression of a spliced variant of the CYP26B1 gene.

    Methodology/Principal Findings

    The coding region of the spliced CYP26B1 lacking exon 2 was amplified from cDNA synthesized from atRA-treated human aortic smooth muscle cells and sequenced. Both the spliced variant and full length CYP26B1 was found to be expressed in cultured human endothelial and smooth muscle cells, and in normal and atherosclerotic vessel. atRA induced both variants of CYP26B1 in cultured vascular cells. Furthermore, the levels of spliced mRNA transcript were 4.5 times higher in the atherosclerotic lesion compared to normal arteries and the expression in the lesions was increased 20-fold upon atRA treatment. The spliced CYP26B1 still has the capability to degrade atRA, but at an initial rate one-third that of the corresponding full length enzyme. Transfection of COS-1 and THP-1 cells with the CYP26B1 spliced variant indicated either an increase or a decrease in the catabolism of atRA, probably depending on the expression of other atRA catabolizing enzymes in the cells.

    Conclusions/Significance

    Vascular cells express the spliced variant of CYP26B1 lacking exon 2 and it is also increased in atherosclerotic lesions. The spliced variant displays a slower and reduced degradation of atRA as compared to the full-length enzyme. Further studies are needed, however, to clarify the substrate specificity and role of the CYP26B1 splice variant in health and disease.

  • 11.
    Eriksson, Leif A.
    et al.
    Göteborgs universitet, Göteborg.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences.
    Strid, Åke
    Örebro University, School of Science and Technology.
    Tetrazole derivatives as cytochrome p450 inhibitors2019Patent (Other (popular science, discussion, etc.))
    Abstract [en]

    According to the invention there is provided a compound of formula I, wherein Rand Rhave meanings given in the description, which compounds are useful in the treatment of skin disorders and other diseases.

  • 12.
    Fransén, Karin
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Franzén, Petra
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Magnuson, Anders
    Örebro University Hospital, Örebro, Sweden.
    Elmabsout, Ali
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Nyhlin, Nils
    Örebro University Hospital.
    Wickbom, Anna
    Örebro University Hospital, Örebro, Sweden.
    Curman, Bengt
    Örebro University Hospital, Örebro, Sweden.
    Törkvist, Leif
    Karolinska University Hospital, Stockholm, Sweden.
    D'Amato, Mauro
    Karolinska University Hospital, Stockholm, Sweden.
    Bohr, Johan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Halfvarson, Jonas
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital.
    Polymorphism in the retinoic acid metabolizing enzyme CYP26B1 and the development of Crohn's disease2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 8, p. e72739-Article in journal (Refereed)
    Abstract [en]

    Several studies suggest that Vitamin A may be involved in the pathogenesis of inflammatory bowel disease (IBD), but the mechanism is still unknown. Cytochrome P450 26 B1 (CYP26B1) is involved in the degradation of retinoic acid and the polymorphism rs2241057 has an elevated catabolic function of retinoic acid, why we hypothesized that the rs2241057 polymorphism may affect the risk of Crohn's disease (CD) and Ulcerative Colitis (UC). DNA from 1378 IBD patients, divided into 871 patients with CD and 507 with UC, and 1205 healthy controls collected at Örebro University Hospital and Karolinska University Hospital were analyzed for the CYP26B1 rs2241057 polymorphism with TaqMan® SNP Genotyping Assay followed by allelic discrimination analysis. A higher frequency of patients homozygous for the major (T) allele was associated with CD but not UC compared to the frequency found in healthy controls. A significant association between the major allele and non-stricturing, non-penetrating phenotype was evident for CD. However, the observed associations reached borderline significance only, after correcting for multiple testing. We suggest that homozygous carriers of the major (T) allele, relative to homozygous carriers of the minor (C) allele, of the CYP26B1 polymorphism rs2241057 may have an increased risk for the development of CD, which possibly may be due to elevated levels of retinoic acid. Our data may support the role of Vitamin A in the pathophysiology of CD, but the exact mechanisms remain to be elucidated.

  • 13.
    Fransén, Karin
    et al.
    Örebro University, School of Medical Sciences.
    Paramel Varghese, Geena
    Örebro University, School of Medical Sciences.
    Jansson, J.H.
    Skellefteå Hospital, Skellefteå, Sweden; Umeå University Hospital, Umeå, Sweden.
    Eriksson, P.
    Karolinska University Hospital , Karolinska Institutet, Stockholm, Sweden.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences.
    Molecular genetic aspects of the NLRP3 inflammasome in cardiovascular disease2016Conference paper (Refereed)
  • 14.
    Fälker, Knut
    et al.
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Ljungberg, Liza
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Kardeby, Caroline
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Lindkvist, Madelene
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Sirsjö, Allan
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Grenegård, Magnus
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Adrenoceptor α2A signalling countervails the taming effects of synchronous cyclic nucleotide-elevation on thrombin-induced human platelet activation and aggregation2019In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 59, p. 96-109Article in journal (Refereed)
    Abstract [en]

    The healthy vascular endothelium constantly releases autacoids which cause an increase of intracellular cyclic nucleotides to tame platelets from inappropriate activation. Elevating cGMP and cAMP, in line with previous reports, cooperated in the inhibition of isolated human platelet intracellular calcium-mobilization, dense granules secretion, and aggregation provoked by thrombin. Further, platelet alpha granules secretion and, most relevant, integrin αIIaβ3 activation in response to thrombin are shown to be prominently affected by the combined elevation of cGMP and cAMP. Since stress-related sympathetic nervous activity is associated with an increase in thrombotic events, we investigated the impact of epinephrine in this setting. We found that the assessed signalling events and functional consequences were to various extents restored by epinephrine, resulting in full and sustained aggregation of isolated platelets. The restoring effects of epinephrine were abolished by either interfering with intracellular calcium-elevation or with PI3-K signalling. Finally, we show that in our experimental setting epinephrine likewise reconstitutes platelet aggregation in heparinized whole blood, which may indicate that this mechanism could also apply in vivo.

  • 15. Gidlöf, Andreas C.
    et al.
    Ocaya, Pauline
    Örebro University, School of Health and Medical Sciences.
    Krivospitskaya, Olesya
    Örebro University, Department of Clinical Medicine.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences.
    Vitamin A: a drug for prevention of restenosis/reocclusion after percutaneous coronary intervention?2008In: Clinical Science, ISSN 0143-5221, E-ISSN 1470-8736, Vol. 114, no 1, p. 19-25Article in journal (Refereed)
    Abstract [en]

    The re-establishment of adequate blood flow in a vessel with a reduced lumen due to an atherosclerotic plaque by percutaneous vascular intervention is a well established procedure. However, the long-term outcome of such interventions is negatively influenced by the development of intimal hyperplasia/restenosis. Although extensively researched, this still represents a significant clinical problem. Retinoids, i.e. natural and synthetic derivates of vitamin A, represent a potential therapeutic compound, since they have been shown to influence the vast majority of processes that ultimately lead to reocclusion of the injured vessel. Retinoids exert their effects at the transcriptional level through their nuclear receptors. Targeting multiple processes, i.e. proliferation, migration, extracellular matrix composition and cell differentiation, as well as coagulation/fibrinolysis, should increase their future role in the prevention of restenosis. The purpose of this review is to summarize the diverse effects of retinoids on pathobiological and biological processes activated at sites of vascular injury with particular emphasis on intimal hyperplasia/restenosis after endovascular interventions.

  • 16. Gidlöf, Andreas C.
    et al.
    Ocaya, Pauline
    Örebro University, Department of Clinical Medicine.
    Olofsson, Peder S.
    Törmä, Hans
    Sirsjö, Allan
    Örebro University, Department of Clinical Medicine.
    Differences in retinol metabolism and proliferative response between neointimal and medial smooth muscle cells2006In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 43, no 4, p. 392-398Article in journal (Refereed)
    Abstract [en]

    Vascular disease is multifactorial and smooth muscle cells (SMCs) play a key role. Retinoids have been shown to influence many disease-promoting processes including proliferation and differentiation in the vessel wall. Phenotypic heterogeneity of vascular SMCs is a well-known phenomenon and phenotypic modulation of SMCs precedes intimal hyperplasia. The SMCs that constitute the intimal hyperplasia demonstrate a distinct phenotype and differ in gene expression compared to medial SMCs. Cellular retinol-binding protein-1 (CRBP-I), involved in retinoid metabolism, is highly expressed in intimal SMCs, indicating altered retinoid metabolism in this subset of cells. The aim of this study was to evaluate the metabolism of all-trans ROH (atROH), the circulating prohormone to active retinoids, in vascular SMCs of different phenotypes. The results show an increased uptake of atROH in intimal SMCs compared to medial SMCs as well as increased expression of the retinoid-metabolizing enzymes retinol dehydrogenase-5 and retinal dehydrogenase-1 and, in conjunction with this gene expression, increased production of all-trans retinoic acid (atRA). Furthermore, the retinoic acid-catabolizing enzyme CYP26A1 is expressed at higher levels in medial SMCs compared to intimal SMCs. Thus, both retinoid activation and deactivation processes are in operation. To analyze if the difference in ROH metabolism was also correlated to differences in the biological response to retinol, the effects of ROH on proliferation of SMCs with this phenotypic heterogeneity were studied. We found that intimal SMCs showed a dose- and time-dependent growth inhibition when treated with atROH in contrast to medial SMCs, in which atROH had a mitogenic effect. This study shows, for the first time, that (1) vascular SMCs are able to synthesize biologically active atRA from the prohormone atROH, (2) intimal SMCs have a higher capacity to internalize atROH and metabolize atROH into atRA compared to medial SMCs and (3) atROH inhibits growth of intimal SMCs, but induces medial SMC growth.

  • 17. Hosseini, Abolfazl
    et al.
    Koskela, Lotta Renström
    Ehrén, Ingrid
    Aguilar-Santelises, Miguel
    Sirsjö, Allan
    Örebro University, Department of Clinical Medicine.
    Wiklund, N. Peter
    Enhanced formation of nitric oxide in bladder carcinoma in situ and in BCG treated bladder cancer2006In: Nitric oxide, ISSN 1089-8603, E-ISSN 1089-8611, Vol. 15, no 4, p. 337-343Article in journal (Refereed)
    Abstract [en]

    The purpose of the study was to analyze endogenous nitric oxide (NO) formation and NO-synthase (NOS) gene expression in the urinary bladder from patients with urinary bladder cancer and to investigate the relationship between local NO formation, treatment with Bacillus Calmette Guerin (BCG) and clinical stage in bladder cancer patients. One hundred and three patients with bladder cancer were studied. Endogenous formation of NO was measured in 72 patients, including 6 patients with BCG treated bladder cancer and 6 tumor free control subjects. iNOS expression was analyzed at transcriptional and protein level in biopsies from 31 patients with bladder cancer by real time polymerase chain reaction (PCR) and Western blot (WB), respectively. Three patients in this group had received BCG treatment. Eight biopsies from normal bladder served as control for PCR and WB analysis. Patients with carcinoma in situ (CIS) had higher iNOS expression (p<0.01) and NO formation (p<0.01) than control subjects and patients with papillary tumors without concomitant CIS. Markedly increased iNOS expression (p<0.05) and NO formation (p<0.001) were also found in patients treated with BCG as compared to the other groups. In conclusion, the presence of elevated NO concentration and iNOS expression in the urinary bladder from BCG treated patients and patients with CIS further supports the notion that NO may be an important factor in bladder cancer biology and that the BCG effect on superficial bladder cancer may partly be due to stimulation of local NO formation.

  • 18.
    Jatta, Ken
    et al.
    Örebro University, School of Health and Medical Sciences.
    Eliason, Gabriella
    Örebro University, School of Health and Medical Sciences.
    Portela-Gomes, Guida M.
    Grimelius, Lars
    Caro, Oscar
    Nilholm, Lennart
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences.
    Piehl-Aulin, Karin
    Örebro University, School of Health and Medical Sciences.
    Abdel-Halim, Samy M.
    Örebro University, School of Health and Medical Sciences.
    Overexpression of von Hippel-Lindau protein in skeletal muscles of patients with chronic obstructive pulmonary disease2009In: Journal of Clinical Pathology, ISSN 0021-9746, E-ISSN 1472-4146, Vol. 62, no 1, p. 70-76Article in journal (Refereed)
    Abstract [en]

    Background/aim: A Significant number of patients with chronic obstructive pulmonary disease (COPD) exhibit skeletal muscle wasting and decreased capillary area formation which have been correlated to increased mortality. The current study aimed to determine the molecular mechanisms mediating decreased capillary formation in COPD.

    Methods: Twenty-four COPD patients and twelve matching controls were recruited. COPD patients were divided into mild, moderate and severe groups according to GOLD (Global Initiative for Chronic Obstructive Lung Disease) criteria. Skeletal muscle biopsies were obtained from the tibialis anterior muscle. Fibre typing and capillary formation together with messenger RNA (mRNA) expression of hypoxia-inducible factors (HIF-1á and HIF-3á ), vascular endothelial growth factors (VEGF-A, -B and -C isoforms) and von Hippel Lindau (VHL) were determined. VHL expression and localization was further studied by immunohistochemistry.

    Results: Skeletal muscle capillary formation was significantly decreased with ascending disease severity. Compared to controls, a tendency to mRNA overexpression of HIF-1á, HIF-3á and VEGF isoforms was observed at mild and moderate COPD that decreased at the severe stage. By contrast, skeletal muscle biopsies from COPD patients exhibited significant overexpression of VHL both on the mRNA and protein levels by immunohistochemistry. VHL protein was further determined to be localized to satellite cells.

    Conclusions: Overexpression of VHL was identified in the skeletal muscle of patients with COPD. Increased VHL activity may exert a negative impact on transducing the hypoxic signal and may contribute to decreased capillarization in skeletal muscles of patients with COPD.

  • 19.
    Jatta, Ken
    et al.
    Örebro University, Department of Clinical Medicine.
    Olofsson, Peder
    Ghaderi, Mehran
    Samnegård, Ann
    Eriksson, Per
    Sirsjö, Allan
    Örebro University, Department of Clinical Medicine.
    Interleukin-1 receptor antagonist and the relation to cardiovascular diseaseManuscript (Other academic)
  • 20.
    Jatta, Ken
    et al.
    Örebro University, Department of Clinical Medicine.
    Wågsäter, Dick
    Örebro University, Department of Clinical Medicine.
    Norgren, Lars
    Stenberg, Björn
    Sirsjö, Allan
    Örebro University, Department of Clinical Medicine.
    Lipopolysaccharide-induced cytokine and chemokine expression in human carotid lesions2005In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 42, no 3, p. 266-271Article in journal (Refereed)
    Abstract [en]

    The release of cytokines and chemokines from activated immune-competent cells plays a crucial role in determining the pathology of the atherogenic progress. We investigated the effect of bacterial lipopolysaccharide (LPS) on cytokine/chemokine expression in carotid lesions and normal renal arteries. The lesions or renal arteries were incubated for 6 h at 37 degrees C in serum-free media treated with or without LPS. After LPS treatment, increased protein levels of IL-1beta, IL-6, IL-8, IL-10, TNF-alpha and MCP-1 were observed in the culture medium from the lesions measured with cytometric bead array. We were able to detect the induction of IL-1beta, IL-6, IL-8, IL-10, TNF-alpha and MCP-1 mRNA in the lesions after stimulation with LPS using real-time PCR. In renal arteries, LPS also induces mRNA expression of all chemokines and cytokines investigated with the exception of IL-6. However, LPS induces significantly higher levels of TNF-alpha, IL-1beta and IL-10 mRNA in lesions compared to renal arteries. The results suggest that infectious agents are capable of enhancing the production of cytokines/chemokines in an already ongoing inflammatory process such as in atherosclerosis, and that low levels of circulating LPS may affect the levels of pro-inflammatory cytokines much more in atherosclerotic vessels than in normal vessels and may contribute to the development of the atherosclerotic lesion.

  • 21.
    Johansson, Jessica
    et al.
    Örebro University, School of Health and Medical Sciences. Department of Clinical Medicine, Örebro University Hospital, Örebro, Sweden.
    Vumma, Ravi
    Örebro University, School of Health and Medical Sciences. Department of Clinical Medicine, Örebro University Hospital, Örebro, Sweden.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences. Department of Clinical Medicine, Örebro University Hospital, Örebro, Sweden.
    Venizelos, Nikolaos
    Örebro University, School of Health and Medical Sciences. Department of Clinical Medicine, Örebro University Hospital, Örebro, Sweden.
    Interleukin-1beta inhibits tyrosine transport in fibroblasts from patients with schizophrenia and healthy controls2010In: Abstracts of, International Institute of Anticancer Research, 2010, no 3, p. 365-367, article id 45Conference paper (Refereed)
  • 22.
    Kardeby, Caroline
    et al.
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Paramel Varghese, Geena
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Pournara, Dimitra
    National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
    Fotopoulou, Theano
    National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Koufaki, Maria
    National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
    Fransén, Karin
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Grenegård, Magnus
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibitionManuscript (preprint) (Other academic)
  • 23.
    Kardeby, Caroline
    et al.
    Örebro University, School of Medical Sciences.
    Paramel Varghese, Geena
    Örebro University, School of Medical Sciences.
    Pournara, Dimitra
    National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
    Fotopoulou, Theano
    National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences.
    Koufaki, Maria
    National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
    Fransén, Karin
    Örebro University, School of Medical Sciences.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences.
    A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition2019In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 857, article id 172428Article in journal (Refereed)
    Abstract [en]

    Natural purines like ATP, ADP and adenosine have crucial roles in platelet physiology. This knowledge has been significant in drug development and today ADP receptor antagonists are widely used for prevention of thrombotic events following myocardial infarction and ischaemic stroke.

    Recent studies have shown that a purine analogue bearing nitrate ester group (denoted MK128) has anti-inflammatory effects probably due to its ability to donate nitric oxide (NO). However, other pharmacological mechanisms may contribute to the observed effect. The aim of the present study was to establish the anti-platelet activity and elucidate the underlying molecular mechanism(s) of the purine analogue MK128.

    We found that MK128 reduced aggregation and secretion induced by the thrombin receptor agonist SFLLRN and nearly abolished aggregation and secretion induced by thromboxane A2 (TxA2) and collagen receptor agonists. The inhibition took place despite blockage of the NO/cGMP signalling system. Furthermore, interaction between MK128 and platelet purinergic receptors did not explain the observed inhibition. Instead, we found that MK128 concentration-dependently inhibited Rho-associated kinase (ROCK), which led to decreased ROCK-dependent myosin phosphatase target subunit (MYPT)-1 phosphorylation and suppression of platelet functional responses.

  • 24.
    Kardeby, Caroline
    et al.
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Sirsjö, Allan
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Ljungberg, Liza
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Grenegård, Magnus
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Sulfated glycopolymers and polysaccharides regulate inflammation-related proteins in human vascular endothelial cellsManuscript (preprint) (Other academic)
  • 25.
    Karlsson, Magnus
    et al.
    Örebro University, School of Science and Technology.
    Strid, Åke
    Örebro University, School of Science and Technology.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences.
    Eriksson, Leif A.
    Örebro University, School of Science and Technology.
    Homology Models and Molecular Modeling of Human Retinoic Acid Metabolizing Enzymes Cytochrome P450 26A1 (CYP26A1) and P450 26B1 (CYP26B1)2008In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 4, no 6, p. 1021-1027Article in journal (Refereed)
    Abstract [en]

    Homology models of cytochrome P450 26A1 and cytochrome P450 26B1 were constructed using the crystal structures of human, CYP2C8, CYP2C9, and CYP3A4 as templates for the model building. The homology models generated were investigated for their docking capacities against the natural substrate all-trans-retinoic acid (atRA), five different tetralone-derived retinoic acid metabolizing blocking agents (RAMBAs), and R115866. Interaction energies (IE) and linear interaction energies (LIE) were calculated for all inhibitors in both homology models after molecular dynamics (MD) simulation of the enzyme-ligand complexes. The results revealed that the homologues had the capacity to distinguish between strong and weak inhibitors. Important residues in the active site were identified from the CYP26A1/B1-atRA complexes. Residues involved in hydrophobic interactions with atRA were Pro113, Phe222, Phe299, Val370,

    Pro371, and Phe374 in CYP26A1 and Leu88, Pro118, Phe222, Phe295, Ile368, and Tyr272 in CYP26B1. Hydrogen bonding interactions were observed between the atRA carboxylate group and Arg 90 in CYP26A1 and with Arg76, Arg95, and Ser369 in CYP26B1.

  • 26.
    Krivospitskaya, Olesya
    et al.
    Örebro University, School of Health and Medical Sciences.
    Elmabsout, Ali Ateia
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Sundman, Eva
    Department of Anesthesiology, Surgical Services and Intensive Care Medicine, Karolinska University Hospital Solna, Stockholm, Sweden; Karolinska Institutet, Stockholm, Sweden.
    Söderström, Leif A.
    Department of Anesthesiology, Surgical Services and Intensive Care Medicine, Karolinska University Hospital Solna, Stockholm, Sweden; Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Ovchinnikova, Olga
    Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Gidlöf, Andreas C.
    Department of Anesthesiology, Surgical Services and Intensive Care Medicine, Karolinska University Hospital Solna, Stockholm, Sweden; Karolinska Institutet, Stockholm, Sweden.
    Scherbak, Nikolai
    Örebro University, School of Science and Technology.
    Norata, Giuseppe Danilo
    Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Pharmacological Sciences University of Milan, Milan, Italy.
    Samnegård, Ann
    Division of Cardiovascular Medicine, Department of Clinical Sciences, Danderyd Hospital, Stockholm, Sweden; Karolinska Institutet, Stockholm, Sweden.
    Törmä, Hans
    Department of Medical Sciences/Dermatology, Uppsala University, Uppsala, Sweden.
    Abdel-Halim, Samy M.
    Division of Respiratory Medicine and Allergology, Department of Clinical Sciences, Danderyd Hospital, Stockholm, Sweden; Karolinska Institutet, Stockholm, Sweden.
    Jansson, Jan-Håkan
    Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden; Department of Medicine, Skellefteå Hospital, Skellefteå, Sweden.
    Eriksson, Per
    Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Olofsson, Peder S.
    Department of Anesthesiology, Surgical Services and Intensive Care Medicine, Karolinska University Hospital Solna, Stockholm, Sweden; Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, North Shore–Long Island Jewish (LIJ) Health System, New York, United States of America.
    A CYP26B1 polymorphism enhances retinoic acid catabolism and may aggravate atherosclerosis2012In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 18, no 1, p. 712-718Article in journal (Refereed)
    Abstract [en]

    All-trans retinoic acid, controlled by CYP26 enzymes, potentially has beneficial effects in atherosclerosis treatment. This study investigates CYP26B1 in atherosclerosis and effects of a genetic polymorphism in CYP26B1 on retinoid catabolism. We found that CYP26B1 mRNA was induced by retinoic acid in human atherosclerotic arteries and CYP26B1 and the macrophage marker CD68 co-localized in human atherosclerotic lesions. In mice, Cyp26B1 mRNA was higher in atherosclerotic than normal arteries. Databases were queried for non-synonymous CYP26B1 SNPs and rs2241057 selected for further studies. Constructs of the CYP26B1 variants were created and used for production of purified proteins and transfection of macrophage-like cells. The minor variant catabolized retinoic acid with significantly higher efficiency, indicating that rs2241057 is functional and suggesting reduced retinoid availability in tissues with the minor variant. rs2241057 was investigated in a Stockholm Coronary Atherosclerosis Risk Factor (SCARF) subgroup. The minor allele was associated with slightly larger lesions as determined by angiography. In summary, this study identifies the first CYP26B1 polymorphism that alters CYP26B1 capacity to metabolize retinoic acid. CYP26B1 was expressed in macrophage-rich areas of human atherosclerotic lesions, induced by retinoic acid and increased in murine atherosclerosis. Taken together, the results indicate that CYP26B1 capacity is genetically regulated and suggest that local CYP26B1 activity may influence atherosclerosis.

  • 27.
    Nixon Tangi, Tebeng
    et al.
    Department of Clinical Medicine, School of Health and Medical Science, Örebro University, Örebro, Sweden.
    Elmabsout, Ali Ateia
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Bengtsson, Torbjörn
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fransén, Karin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Role of NLRP3 and CARD8 in the regulation of TNF-α induced IL-1β release in vascular smooth muscle cells2012In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 30, no 3, p. 697-702Article in journal (Refereed)
    Abstract [en]

    Interleukin (IL)-1β is known to be activated by the inflammasome. Inflammasome activities depend on a plethora of moieties including NLRP3 and CARD8, which have been reported to be associated with several inflammatory diseases. Aortic smooth muscle cells (AOSMCs) were transfected with siRNA targeting the NLRP3 and CARD8 genes, followed by tumor necrosis factor-α (TNF-α) treatment. We found that TNF-α induces IL-1β, IL-1Ra and NLRP3 genes but not CARD8. Silencing of the NLRP3 gene significantly decreased IL-1β expression and release, the IL-1Ra expression showed a borderline non-significant increment, while CARD8 knockdown did not affect the IL-1β and IL-1Ra mRNA expression or IL-1β protein release. Our results suggest that mainly NLRP3 plays a role in the regulation of IL-1β expression and release in AOSMC and could be a potential future target for the treatment of atherosclerosis and other inflammatory diseases.

  • 28.
    Ocaya, Pauline A.
    et al.
    Örebro University, Department of Clinical Medicine.
    Gidlöf, Andreas C.
    Olofsson, Peder S.
    Norgren, Lars
    Törmä, Hans
    Sirsjö, Allan
    Örebro University, Department of Clinical Medicine.
    The importance of CYP26 in the regulation of atRA metabolism in human atherosclerotic lesions and aortic smooth muscle cellsManuscript (Other academic)
  • 29.
    Ocaya, Pauline Ajok
    et al.
    Örebro University, School of Health and Medical Sciences.
    Elmabsout, Ali Ateia
    Örebro University, School of Health and Medical Sciences.
    Olofsson, Peder Stefan
    Dept Anesthesiol & Intens Care Med, Ctr Mol Med, Karolinska Univ Hosp, Karolinska Inst, Stockholm, Sweden .
    Törmä, Hans
    Dept Med Sci Dermatol, Uppsala Univ, Uppsala, Sweden.
    Gidlöf, Andreas Carl
    Dept Anesthesiol & Intens Care Med, Ctr Mol Med, Karolinska Univ Hosp, Karolinska Inst, Stockholm, Sweden.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences.
    CYP26B1 plays a major role in the regulation of all-trans-retinoic acid metabolism and signaling in human aortic smooth muscle cells2011In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 48, no 1, p. 23-30Article in journal (Refereed)
    Abstract [en]

    Aim: The cytochrome P450 enzymes of the CYP26 family are involved in the catabolism of the biologically active retinoid all-trans-retinoic acid (atRA). Since it is possible that an increased local CYP26 activity would reduce the effects of retinoids in vascular injury, we investigated the role of CYP26 in the regulation of atRA levels in human aortic smooth muscle cells (AOSMCs).

    Methods: The expression of CYP26 was investigated in cultured AOSMCs using real-time PCR. The metabolism of atRA was analyzed by high-performance liquid chromatography, and the inhibitor R115866 or small interfering RNA (siRNA) was used to suppress CYP26 activity/expression.

    Results: AOSMCs expressed CYP26B1 constitutively and atRA exposure augmented CYP26B1 mRNA levels. Silencing of the CYP26B1 gene expression or reduction of CYP26B1 enzymatic activity by using siRNA or the inhibitor R115866, respectively, increased atRA-mediated signaling and resulted in decreased cell proliferation. The CYP26 inhibitor also induced expression of atRA-responsive genes. Therefore, atRA-induced CYP26 expression accelerated atRA inactivation in AOSMCs, giving rise to an atRA-CYP26 feedback loop. Inhibition of this loop with a CYP26 inhibitor increased retinoid signaling.

    Conclusion: The results suggest that CYP26 inhibitors may be a therapeutic alternative to exogenous retinoid administration. Copyright (C) 2010 S. Karger AG, Basel

  • 30.
    Ocaya, Pauline
    et al.
    Örebro University, Department of Clinical Medicine.
    Gidlöf, Andreas C.
    Olofsson, Peder S.
    Törmä, Hans
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences.
    CYP26 inhibitor R115866 increases retinoid signaling in intimal smooth muscle cells2007In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 27, no 7, p. 1542-1548Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Intimal smooth muscle cells (SMCs) are dedifferentiated SMCs that have a powerful ability to proliferate and migrate. This cell-type is responsible for the development of intimal hyperplasia after vascular angioplasty. Retinoids, especially all-trans retinoid acid, are known to regulate many processes activated at sites of vascular injury, including modulation of SMC phenotype and inhibition of SMC proliferation. Intracellular levels of active retinoids are under firm control. A key enzyme is the all-trans retinoic acid-degrading enzyme cytochrome p450 isoform 26 (CYP26). Thus, an alternative approach to exogenous retinoid administration could be to increase the intracellular level of all-trans retinoic acid by blocking CYP26-mediated degradation of retinoids.

    METHODS AND RESULTS: Vascular intimal and medial SMCs expressed CYP26A1 and B1 mRNA. Although medial cells remained unaffected, treatment with the CYP26-inhibitor R115866 significantly increased cellular levels of all-trans retinoic acid in intimal SMCs. The increased levels of all-trans retinoic acid induced retinoid-regulated genes and decreased mitogenesis.

    CONCLUSIONS: Blocking of the CYP26-mediated catabolism mimics the effects of exogenously administrated active retinoids on intimal SMCs. Therefore, CYP26-inhibitors offer a potential new therapeutic approach to vascular proliferative disorders.

  • 31. Olofsson, P. S.
    et al.
    Sheikine, Y.
    Jatta, Ken
    Örebro University, School of Health and Medical Sciences.
    Ghaderi, M.
    Samnegård, A.
    Eriksson, P.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences.
    A functional interleukin-1 receptor antagonist polymorphism influences atherosclerosis development - The interleukin-1β: Interleukin-1 receptor antagonist balance in atherosclerosis2009In: Circulation Journal, ISSN 1346-9843, E-ISSN 1347-4820, Vol. 73, no 8, p. 1531-1536Article in journal (Refereed)
    Abstract [en]

    Background: Interleukin (JL)-β plays a central role in inflammation and atherosclerosis, but levels of IL-1β, its natural antagonist, IL-1Ra, and their balance in human atherosclerotic lesions, are unknown. Knowledge of protein levels in atherosclerosis and the influence of a functional IL-1Rα polymorphism would increase the understanding of atherosclerosis pathogenesis.

    Methods and Results: Fresh and endotoxin-stimulated explanted human atherosclerotic and normal arteries were analyzed for IL-1β, IL-1Ra and IL-1 receptor 1 (IL-1R1) using TaqMan PCR and enzyme-linked immunosorbent assay. Two hundred forty-three survivors of a first myocardial infarction were genotyped for a polymorphism in IL-1Ra and their coronary atherosclerosis analyzed by using coronary angiography. Levels of IL-1β, IL-1Ra and IL-1R1 mRNA were significantly increased in atherosclerotic arteries compared with normal arteries. Endotoxin stimulation increased IL-1β levels more than IL-1Ra levels (ie, promoted a pro-inflammatory state). A polymorphism in IL-1Ra known to increase levels of IL-1Ra was associated with decreased mean coronary artery plaque area.

    Conclusions: Activation of innate immunity changed the balance between IL-1β and IL-1Ra in atherosclerotic arteries towards a more pro-inflammatory state. In line with this, the presence of an IL-1Ra intron 2 polymorphism known to increase IL-1Ra levels, and possibly the IL-1Ra:IL-1β ratio, was associated with reduced coronary atherosclerosis.

  • 32. Olofsson, P. S.
    et al.
    Söderström, L. Å.
    Jern, C.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences.
    Ria, M.
    Sundler, E.
    De Faire, U.
    Wiklund, P. G.
    Öhrvik, J.
    Hedin, U.
    Paulsson-Berne, G.
    Hamsten, A.
    Eriksson, P.
    Hansson, G. K.
    Genetic variants of TNFSF4 and risk for carotid artery disease and stroke2009In: Journal of Molecular Medicine, ISSN 0946-2716, E-ISSN 1432-1440, Vol. 87, no 4, p. 337-346Article in journal (Refereed)
    Abstract [en]

    In two independent human cohorts, the minor allele of SNP rs3850641 in TNFSF4 was significantly more frequent in individuals with myocardial infarction than in controls. In mice, Tnfsf4 expression is associated with increased atherosclerosis. The expression of TNFSF4 in human atherosclerosis and the association between genotype and cerebrovascular disease have not yet been investigated. TNFSF4 messenger RNA (mRNA) levels were significantly higher in human atherosclerotic lesions compared with controls (730∈±∈30 vs 330∈±∈65 arbitrary units, p∈<∈0.01). TNFSF4 was mainly expressed by macrophages in atherosclerotic lesions. In cell culture, endothelial cells upregulated TNFSF4 in response to tumor necrosis factor alpha (TNF-α; 460∈±∈110 vs 133∈±∈8 arbitrary units, p∈<∈0.001 after 6 h of stimulation). We analyzed the TNFSF4 gene in 239 patients who had undergone carotid endarterectomy and 138 matching controls from The Biobank of Karolinska Carotid Endarterectomies and Stockholm Heart Epidemiology Program cohorts and 929 patients and 1,382 matching controls from the Sahlgrenska Academy Study on Ischemic Stroke and Case Control Study of Stroke cohorts, limiting inclusion to patients with ischemic stroke. Participants were genotyped for the rs3850641 SNP in TNFSF4. Genotype associations were neither found with TNFSF4 mRNA levels nor with atherosclerosis associated systemic factors or risk for stroke. This study shows that TNFSF4 is expressed on antigen-presenting cells in human carotid atherosclerotic lesions but provides no evidence for an association of TNFSF4 gene variation with the risk for ischemic stroke.

  • 33. Olofsson, Peder
    et al.
    Jatta, Ken
    Örebro University, Department of Clinical Medicine.
    Wågsäter, Dick
    Gredmark, Sara
    Hedin, Ulf
    Paulsson-Berne, Gabrielle
    Söderberg-Nauclér, Cecilia
    Hansson, Göran
    Sirsjö, Allan
    Örebro University, Department of Clinical Medicine.
    The antiviral cytomegalovirus inducible gene 5/viperin is expressed in atherosclerosis and regulated by proinflammatory agents2005In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 25, no 7, p. 113-116Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    Inflammatory processes play an important role in atherosclerosis, and increasing evidence implies that microbial pathogens and proinflammatory cytokines are involved in the development and activation of atherosclerotic lesions. To find new inflammatory genes, we explored the vascular transcriptional response to an activator of innate immunity bacterial lipopolysaccharides (LPSs).

    METHODS AND RESULTS:

    Gene arrays identified the cytomegalovirus-inducible gene 5 (cig5)/viperin among the genes most potently induced by LPS in human vascular biopsies. Viperin was expressed by endothelial cells in atherosclerotic arteries and significantly elevated in atherosclerotic compared with normal arteries. In culture, cytomegalovirus infection, interferon-gamma, and LPS induced viperin expression.

    CONCLUSIONS:

    Viperin is expressed in atherosclerosis and induced in vascular cells by inflammatory stimuli and cytomegalovirus infection. The putative functions of viperin in atherosclerosis may relate to disease-associated microbes.

  • 34. Olofsson, Peder S.
    et al.
    Söderström, Leif A.
    Wågsäter, Dick
    Örebro University, School of Health and Medical Sciences.
    Sheikine, Yuri
    Ocaya, Pauline
    Örebro University, Department of Clinical Medicine.
    Lang, François
    Rabu, Catherine
    Chen, Lieping
    Rudling, Mats
    Aukrust, Pål
    Hedin, Ulf
    Paulsson-Berne, Gabrielle
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences.
    Hansson, Göran K.
    CD137 is expressed in human atherosclerosis and promotes development of plaque inflammation in hypercholesterolemic mice2008In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 117, no 10, p. 1292-1301Article in journal (Refereed)
    Abstract [en]

    Background— Atherosclerosis is a multifactorial disease in which inflammatory processes play an important role. Inflammation underlies lesion evolution at all stages, from establishment to plaque rupture and thrombosis. Costimulatory molecules of the tumor necrosis factor superfamily such as CD40/CD40L and OX40/OX40L have been implicated in atherosclerosis. Methods and Results— This study shows that the tumor necrosis factor superfamily members CD137 and CD137 ligand (CD137L), which play a major role in several autoimmune diseases, may constitute a pathogenic pair in atherogenesis. We detected CD137 protein in human atherosclerotic lesions not only on T cells but also on endothelial cells and showed that CD137 in cultured endothelial cells and smooth muscle cells was induced by proinflammatory cytokines implicated in atherosclerosis. Activation of CD137 by CD137L induced adhesion molecule expression on endothelial cells and reduced smooth muscle cell proliferation. In addition, treatment of atherosclerosis-prone apolipoprotein E–deficient mice with a CD137 agonist caused increased inflammation. T-cell infiltration, mainly of CD8+ cells, and expression of the murine major histocompatibility complex class II molecule I-Ab increased significantly in atherosclerotic lesions, as did the aortic expression of proinflammatory cytokines. Conclusions— Taken together, these observations suggest that CD137-CD137L interactions in the vasculature may contribute to the progression of atherosclerosis via augmented leukocyte recruitment, increased inflammation, and development of a more disease-prone phenotype.

  • 35. Olofsson, Peder S.
    et al.
    Wågsäter, Dick
    Örebro University, Department of Nursing and Caring Sciences.
    Sheikine, Yuri
    Jatta, Ken
    Hansson, Göran K.
    Sirsjö, Allan
    Örebro University, Department of Nursing and Caring Sciences.
    CD137 is expressed on endothelial cells in human atherosclerotic lesions and induced by proinflammatory cytokines and bacterial lipopolysaccharidesManuscript (Other academic)
  • 36.
    Paramel, Geena
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Folkersen, Lasse
    Atherosclerosis Research Unit, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Strawbridge, Rona J.
    Atherosclerosis Research Unit, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Elmabsout, Ali
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Särndahl, Eva
    Örebro University, School of Medicine, Örebro University, Sweden.
    Lundman, Pia
    Division of Cardiovascular Medicine, Department of Clinical Sciences, Karolinska Institutet, Danderyd University Hospital, Stockholm, Sweden.
    Jansson, Jan-Håkan
    Department of Internal Medicine, Skellefteå Hospital, Umeå, Sweden; Department of Internal Medicine, Umeå University Hospital, Umeå, Sweden.
    Hansson, Göran K.
    Experimental Cardiovascular Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fransén, Karin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    CARD8 gene encoding a protein of innate immunity is expressed in human atherosclerosis and associated with markers of inflammation2013In: Clinical Science, ISSN 0143-5221, E-ISSN 1470-8736, Vol. 125, no 8, p. 401-407Article in journal (Refereed)
    Abstract [en]

    Inflammation is a key factor in the development of atherosclerotic coronary artery disease. It is promoted through the inflammasome, a molecular machine that produces IL (interleukin)-1 beta in response to cholesterol crystal accumulation in macrophages. The CARD8 (caspase recruitment domain 8) protein modulates this process by suppressing caspase 1 and the transcription factor NF-kappa B (nuclear factor kappa B). The expression of CARD8 mRNA was examined in atherosclerotic vascular tissue and the impact on MI (myocardial infarction) of a polymorphism in the CARD8 gene determined. CARD8 mRNA was analysed by microarray of human atherosclerotic tissue and compared with transplant donor arterial tissue. Microarray analysis was performed for proximal genes associated with the rs2043211 locus in plaque. The CARD8 rs2043211 polymorphism was analysed by genotyping of two Swedish MI cohorts, FIA (First Myocardial Infarction in Northern Sweden) and SCARF (Stockholm Coronary Atherosclerosis Risk Factor). The CRP (C-reactive protein) level was measured in both cohorts, but the levels of the pro-inflammatory cytokines IL-1 beta, IL-18, TNF (tumour necrosis factor) and MCP-1 (monocyte chemoattractant protein) were measured in sera available from the SCARF cohort. CARD8 mRNA was highly expressed in atherosclerotic plaques compared with the expression in transplant donor vessel (P < 0.00001). The minor allele was associated with lower expression of CARD8 in the plaques, suggesting that CARD8 may promote inflammation. Carriers of the minor allele of the rs2043211 polymorphism also displayed lower circulating CRP and lower levels of the pro-atherosclerotic chemokine MCP-1. However, no significant association could be detected between this polymorphism and MI in the two cohorts. Genetic alterations in the CARD8 gene therefore seem to be of limited importance for the development of MI.

  • 37.
    Paramel, Geena
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fransén, Karin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Hurtig-Wennlöf, Anita
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Bengtsson, Torbjörn
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Jansson, Jan-Håkan
    Department of Internal Medicine, Skellefteå Hospital and Umeå University Hospital.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Q705K variant in NLRP3 gene confers protection against myocardial infarction in female individuals2013In: Biomedical Reports, ISSN 2049-9434, Vol. 1, no 6, p. 879-882Article in journal (Refereed)
    Abstract [en]

    Inflammation is a multifaceted process that underlies the pathophysiology of acute myocardial infarction (MI). Variations in the inflammasome‑related NLRP3 gene have been associated with risk for a number of different inflammatory diseases. Therefore, Q705K polymorphism in NLRP3 gene likely confers susceptibility to risk for MI. A First‑ever myocardial Infarction study in Ac‑county (FIA) cohort comprising 555 MI patients and 1,016 controls was used to genotype rs35829419 in the NLRP3 gene by TaqMan single‑nucleotide polymorphism assay. C‑reactive protein (CRP) was measured in the study participants by ELISA. The results showed no significant association between the variant rs35829419 and MI. However, the minor A allele of the rs35829419 polymorphism conferred a protective effect against the risk of developing MI in females. The minor A allele of rs35829419 polymorphism was also associated with increased CRP levels in males. Results of the study suggested a gender‑specific deregulation of NLRP3 gene mediated by rs35829419 polymorphism that confers protection against MI in females but has no effect on MI susceptibility in males. However, the rs35829419 polymorphism was associated with increased CRP levels among the male subjects, thereby demonstrating the possible effect of the Q705K polymorphism in elevating the basal active state of innate immune response.

  • 38.
    Paramel, Geena
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fransén, Karin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Role of genetic alterations in the NLRP3 and CARD8 genes in health and disease2015In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, article id 846782Article in journal (Refereed)
    Abstract [en]

    The complexity of a common inflammatory disease is influenced by multiple genetic and environmental factors contributing to the susceptibility of disease. Studies have reported that these exogenous and endogenous components may perturb the balance of innate immune response by activating the NLRP3 inflammasome. The multimeric NLRP3 complex results in the caspase-1 activation and the release of potent inflammatory cytokines, like IL-1β. Several studies have been performed on the association of the genetic alterations in genes encoding NLRP3 and CARD8 with the complex diseases with inflammatory background, like inflammatory bowel disease, cardiovascular diseases, rheumatoid arthritis, and type 1 diabetes. The aim of the present review is therefore to summarize the literature regarding genetic alterations in these genes and their association with health and disease.

  • 39.
    Paramel, Geena
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Uporova, Ludmila
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Halfvarson, Jonas
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fransén, Karin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Polymorphism in the NLRP3 inflammasome-associated EIF2AK2 gene and inflammatory bowel disease2015In: Molecular Medicine Reports, ISSN 1791-2997, E-ISSN 1791-3004, Vol. 11, no 6, p. 4579-4584Article in journal (Refereed)
    Abstract [en]

    Inflammatory bowel disease (IBD) is the common name for numerous relapsing inflammatory conditions, and is the collective name for Crohn's disease (CD) and ulcerative colitis (UC). The activation of the inflammasome in the pathogenesis of IBD has recently been identified, however the underlying mechanisms remain unclear. An activator of the inflammasome is double-stranded RNA-dependent protein kinase R, also termed EIF2AK2. A genetic alteration in the EIF2AK2 gene has previously been shown to be associated with Alzheimer's disease. The present study genotyped samples from a Swedish cohort of patients with IBD and healthy controls for an EIF2AK2 polymorphism. The rs2254958 polymorphism in the 5'-untranslated region of the EIF2AK2 gene was genotyped by TaqMan® single nucleotide polymorphism genotyping, followed by allelic discrimination. However, no significant association was determined between the rs2254958 polymorphism and the development of IBD, or clinical outcome. In conclusion, the results of the present study suggest that the rs2254958 polymorphism has a limited effect on the onset or progression of IBD.

  • 40.
    Paramel Varghese, Geena
    et al.
    Örebro University, School of Medical Sciences.
    Folkersen, Lasse
    Department of Medicine and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Strawbridge, Rona J.
    Department of Medicine and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Halvorsen, Bente
    Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
    Yndestad, Arne
    Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammatory Research Center, University of Oslo, Oslo, Norway.
    Ranheim, Trine
    Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
    Krohg-Sørensen, Kirsten
    Department of Thoracic and Cardiovascular Surgery, Oslo University Hospital Rikshospitalet, Oslo, Norway.
    Skjelland, Mona
    Department of Neurology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
    Espevik, Terje
    Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway.
    Aukrust, Pål
    Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; K.G. Jebsen Inflammatory Research Center, University of Oslo, Oslo, Norway.
    Lengquist, Mariette
    Department of Surgery, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Hedin, Ulf
    Department of Surgery, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Jansson, Jan-Håkan
    Department of Internal Medicine, Umeå University Hospital, Umeå, Sweden; Department of Internal Medicine, Skellefteå Hospital, Skellefteå, Sweden.
    Fransén, Karin
    Örebro University, School of Medical Sciences.
    Hansson, Göran K.
    Department of Medicine and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Eriksson, Per
    Department of Medicine and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences.
    NLRP3 Inflammasome Expression and Activation in Human Atherosclerosis2016In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 5, no 5, article id e003031Article in journal (Refereed)
    Abstract [en]

    Background: The NLR family, pyrin domain containing 3 (NLRP3) inflammasome is an interleukin (IL)-1β and IL-18 cytokine processing complex that is activated in inflammatory conditions. The role of the NLRP3 inflammasome in the pathogenesis of atherosclerosis and myocardial infarction is not fully understood.

    Methods and Results: Atherosclerotic plaques were analyzed for transcripts of the NLRP3 inflammasome, and for IL-1β release. The Swedish First-ever myocardial Infarction study in Ac-county (FIA) cohort consisting of DNA from 555 myocardial infarction patients and 1016 healthy individuals was used to determine the frequency of 4 single nucleotide polymorphisms (SNPs) from the downstream regulatory region of NLRP3. Expression of NLRP3, Apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1 (CASP1), IL1B, and IL18 mRNA was significantly increased in atherosclerotic plaques compared to normal arteries. The expression of NLRP3 mRNA was significantly higher in plaques of symptomatic patients when compared to asymptomatic ones. CD68-positive macrophages were observed in the same areas of atherosclerotic lesions as NLRP3 and ASC expression. Occasionally, expression of NLRP3 and ASC was also present in smooth muscle cells. Cholesterol crystals and ATP induced IL-1β release from lipopolysaccharide-primed human atherosclerotic lesion plaques. The minor alleles of the variants rs4266924, rs6672995, and rs10733113 were associated with NLRP3 mRNA levels in peripheral blood mononuclear cells but not with the risk of myocardial infarction.

    Conclusions: Our results indicate a possible role of the NLRP3 inflammasome and its genetic variants in the pathogenesis of atherosclerosis.

  • 41.
    Paramel Varghese, Geena
    et al.
    Örebro University, School of Medical Sciences.
    Göthlin Eremo, Anna
    Örebro University Hospital, Örebro, Sweden.
    Ljungberg, Liza
    Örebro University, School of Medical Sciences.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences.
    Fransén, Karin
    Örebro University, School of Health Sciences.
    CARD8, a protein of innate immunity regulates the release of inflammatory cytokines in human endothelial cellsManuscript (preprint) (Other academic)
  • 42.
    Paramel Varghese, Geena
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Zhang, Boxi
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Khalaf, Hazem
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Ljungberg, Liza U.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Bengtsson, Torbjörn
    Örebro University, School of Medicine, Örebro University, Sweden.
    Fransén, Karin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Poryphyromonas gingivalis induces IL-1β in aortic smooth muscle cells: possible role of gingipains?Manuscript (preprint) (Other academic)
  • 43.
    Saenz-Méndez, Patricia
    et al.
    Computational Chemistry and Biology Group, Facultad de Química, Universidad de la República (UdelaR), Montevideo, Uruguay.
    Elmabsout, Ali Ateia
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Clinical Medicine, School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Sävenstrand, Helena
    Örebro University, School of Science and Technology.
    Awadalla, Mohamed Khalid Alhaj
    Department of Clinical Medicine, School of Health Sciences, Örebro University, Örebro, Sweden.
    Strid, Åke
    Örebro University, School of Science and Technology.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Clinical Medicine, School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Eriksson, Leif A.
    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden.
    Homology models of human all-trans-retinoic acid metabolizing enzymes CYP26B1 and CYP26B1 spliced-variant2012In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 52, no 10, p. 2631-2637Article in journal (Refereed)
    Abstract [en]

    Homology models of CYP26B1 (cytochrome P450RAI2) and CYP26B1 spliced-variant were derived using the crystal structure of cyanobacterial CYP120A1 as template for the model building. The quality of the homology models generated were carefully evaluated, and the natural substrate all-trans-retinoic acid (atRA), several tetralone-derived retinoic acid metabolizing blocking agents (RAMBAs) and a well known potent inhibitor of CYP26B1 (R115866) were docked into the homology model of full-length cytochrome P450 26B1. The results show that in the model of the full length CYP26B1, the protein is capable of distinguishing between the natural substrate (atRA), R115866 and the tetralone derivatives. The spliced-variant of CYP26B1 model displays a reduced affinity for atRA compared to the full length enzyme, in accordance with recently described experimental information.

  • 44. Sheikine, Yuri
    et al.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences.
    CXCL16/SR-PSOX: a friend or a foe in atherosclerosis?2008In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 197, no 2, p. 487-495Article in journal (Refereed)
    Abstract [en]

    Chemokines, scavenger receptors and adhesion molecules have long been known as important players in the pathogenesis of atherosclerosis. A series of studies conducted in the past few years described CXCL16/SR-PSOX—a new molecule combining those three functions, and suggested that CXCL16/SR-PSOX can be a potential player in atherogenesis. Initial ex vivo studies showed that CXCL16/SR-PSOX is abundant in human and murine atherosclerotic lesions. Following in vitro studies suggested that as an adhesion molecule CXCL16/SR-PSOX might mediate T-cell adhesion to the endothelium, as a chemokine – drive T-cell migration, stimulate cell proliferation and elicit inflammatory phenotype in smooth muscle cells (SMC) and, finally, as a scavenger receptor – mediate uptake of atherogenic lipoproteins by macrophages and SMC. All these effects are known to be pro-atherogenic. Surprisingly, in vivo studies performed in murine models of atherosclerosis suggested that CXCL16/SR-PSOX is atheroprotective, while its receptor CXCR6 is harmful. In addition, studies investigating the association of circulating CXCL16/SR-PSOX plasma concentrations with the presence and extent of coronary artery disease (CAD) in humans are controversial suggesting both positive, negative and no association. To finally answer the question whether CXCL16/SR-PSOX can serve as a causative factor, biomarker or even a therapeutic target in atherosclerosis, we are currently in need of carefully designed animal and human studies investigating the effects of CXCL16/SR-PSOX and CXCR6 deficiency, inhibition and over-expression on the progression of atherosclerosis. Such complex approach will help us unravel the mystery of CXCL16/SR-PSOX in atherosclerosis and hopefully develop better ways of treating atherosclerosis by targeting this interesting molecule.

  • 45.
    Uggla, Bertil
    et al.
    Department of Medicine, Örebro University Hospital, Örebro; Karolinska Institute, Stockholm.
    Ståhl, Elisabet
    Clinical Research Centre, Örebro University Hospital, Örebro.
    Wågsäter, Dick
    Örebro University, Department of Nursing and Caring Sciences.
    Paul, Christer
    Department of Haematology, Huddinge University Hospital, Stockholm; Karolinska Institute, Stockholm.
    Karlsson, Mats G.
    Department of Pathology, Örebro University Hospital, Örebro.
    Sirsjö, Allan
    Örebro University, Department of Nursing and Caring Sciences.
    Tidefelt, Ulf
    Örebro University, Department of Clinical Medicine. Department of Medicine, Örebro University Hospital, Örebro.
    BCRP mRNA expression v. clinical outcome in 40 adult AML patients2005In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 29, no 2, p. 141-146Article in journal (Refereed)
    Abstract [en]

    Efflux pumps are considered being mechanisms behind drug resistance in acute myeloid leukaemia (AML). A recently described efflux pump, breast cancer resistance protein (BCRP), can be expressed in AML, but its clinical importance is uncertain. In this study BCRP mRNA expression was determined in samples from 40 AML patients by real-time RT-PCR. The expression varied from negative to 76 times that of control cells. There was no difference in BCRP mRNA expression between patients responding to induction treatment and non-responders. However, in the group of responders, the 14 patients with the highest expression had significantly shorter overall survival (mean 38 months, SEM 15 months) than the 14 patients with the lowest (74 months, SEM 16 months) (P = 0.047). This suggests a possible role of BCRP in drug resistance in AML.

  • 46.
    Uggla, Bertil
    et al.
    Department of Medicine, Örebro University Hospital, Örebro.
    Tina, Elisabet
    Clinical Research Centre, Örebro University Hospital, Örebro.
    Nahi, Hareth
    Department of Clinical Hematology, Karolinska University Hospital, Huddinge, Stockholm; Karolinska Institute, Stockholm.
    Paul, Christer
    Department of Clinical Hematology, Karolinska University Hospital, Huddinge, Stockholm; Karolinska Institute, Stockholm.
    Höglund, Martin
    Department of Haematology, Uppsala University Hospital, Uppsala,.
    Sirsjö, Allan
    Örebro University, Department of Clinical Medicine.
    Tidefelt, Ulf
    Örebro University, Department of Clinical Medicine. Department of Medicine, Örebro University Hospital, Örebro.
    Topoisomerase IIα mRNA and protein expression vs. in vitro drug resistance and clinical outcome in acute leukaemia2007In: International Journal of Oncology, ISSN 1019-6439, Vol. 31, no 1, p. 153-160Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to correlate the expression of topoisomerase (topo) IIalpha to in vitro drug sensitivity and to the clinical outcome in patients with acute leukaemia. Leukaemic cells were isolated from bone marrow or blood from 94 patients. Topo IIalpha mRNA (n=58) and protein (n=60) expression was determined by real-time RT-PCR and flow cytometry, respectively. In both groups, chemosensitivity testing by a bioluminescence ATP assay was performed to a variable extent for both topo IIalpha poisons and non-topo IIalpha targeting drugs. Topo IIalpha mRNA expression varied with relative values ranging from 0.03 to 14.20 (median 1.10). The median value for topo IIalpha protein-positive cells was 23% (range 0-99%). Cell samples from patients with a high (>median value) percentage of topo IIalpha-positive cells were significantly more sensitive to the topo IIalpha active drugs etoposide and daunorubicin, and showed a borderline value for idarubicin (p=0.08), while there was no difference for non-topo IIalpha targeting drugs. However, we did not find any significant differences in mRNA expression or the percentage of topo IIalpha-positive cells in patients who achieved complete remission after at most two induction courses compared with those who did not, nor did we find any difference in survival when patients with high mRNA expression/percentage of topo IIalpha-positive cells were compared with patients with low values. We conclude that expression of topo IIalpha, determined as percentage of topo IIalpha-positive cells, in leukaemic cells correlates to chemosensitivity in vitro against topoisomerase poisons but that it does not predict clinical outcome in acute leukaemia.

  • 47.
    Virtanen, Marie
    et al.
    Dept Med Sci, Uppsala Univ, Uppsala, Sweden.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences.
    Vahlquist, Anders
    Dept Med Sci, Uppsala Univ, Uppsala, Sweden.
    Torma, Hans
    Dept Med Sci, Uppsala Univ, Uppsala, Sweden.
    Keratins 2 and 4/13 in reconstituted human skin are reciprocally regulated by retinoids binding to nuclear receptor RAR alpha2010In: Experimental dermatology, ISSN 0906-6705, E-ISSN 1600-0625, Vol. 19, no 7, p. 674-681Article in journal (Refereed)
    Abstract [en]

    Disorders of keratinization are often treated with vitamin A derivatives (retinoids) which affect keratinocyte differentiation, including keratin (KRT) gene expression. In vivo, suprabasal keratinocytes normally express only keratin (K) 1, K2 and K10, but after topical application of all-trans retinoic acid (ATRA), the granular cells will additionally express K4 and K13, i.e. keratins normally present in oral mucosa and in cultured epidermal keratinocytes. To learn more about the retinoid regulation of keratin expression under in vivo-like conditions, we cultured keratinocytes on de-epidermized dermis in only 0.5% serum. These cells produce a normal-looking epidermis that expresses high mRNA levels of KRT1, KRT2 and KRT10, but minimal amounts of KRT4 and KRT13. Addition of ATRA to the medium for 48 h caused a dose-dependent increase in KRT4/KRT13 and a down-regulation of KRT2 mRNA. An increase in K4 protein was also found. The response was greater than the up-regulation of another retinoid-regulated gene, CRABPII. By studying 10 retinoids with different affinities for the retinoic acid receptors (RAR) and retinoid X receptors (RXR) isoforms, the reciprocal expression of KRT2 and KRT4/KRT13 could be connected with agonists for RAR alpha. Two of these agonists, CD336/Am580 and CD2081, altered the expression profile with similar potency as the pan-RAR agonists ATRA and CD367. Co-addition of a pan-RAR antagonist (CD3106/AGN193109) markedly inhibited the induction of KRT4/KRT13 expression, whereas the down-regulation of KRT2 was less affected. In conclusion, RAR alpha agonists elicit a reciprocal modulation of KRT2 and KRT4/KRT13 expression in human epidermis, but whether or not the keratin genes also possess RAR alpha-specific regulatory elements is still unclear.

  • 48. Wuttge, Dirk M.
    et al.
    Zhou, Xinghua
    Sheikine, Yuri
    Wågsäter, Dick
    Örebro University, Department of Nursing and Caring Sciences.
    Stemme, Veronika
    Hedin, Ulf
    Stemme, Sten
    Hansson, Göran K.
    Sirsjö, Allan
    Örebro University, Department of Nursing and Caring Sciences.
    CXCL16/SR-PSOX is an interferon-gamma-regulated chemokine and scavenger receptor expressed in atherosclerotic lesions2004In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 24, no 4, p. 750-755Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Atherosclerosis is an inflammatory disease. Several chemokines are important for monocyte/macrophage and T-cell recruitment to the lesion. CXCL16 is a recently discovered chemokine that is expressed in soluble and transmembrane forms, ligates CXCR6 chemokine receptor, and guides migration of activated Th1 and Tc1 cells. It is identical to scavenger receptor SR-PSOX, which mediates uptake of oxidized low-density lipoprotein. We investigated whether CXCL16 expression is controlled by interferon-gamma (IFN-gamma)-cytokine abundant in atherosclerotic lesions. METHODS AND RESULTS: CXCL16 and CXCR6 expression was identified by polymerase chain reaction and histochemistry in atherosclerotic lesions from humans and apolipoprotein-E-deficient mice. In vitro IFN-gamma induced CXCL16 in human monocytic THP-1 cells and primary human monocytes, which led to increased uptake of oxidized low-density lipoprotein in THP-1 cells, which could be blocked by peptide antibodies against CXCL16. In vivo IFN-gamma induced CXCL16 expression in murine atherosclerotic lesions. CONCLUSIONS: We demonstrate a novel role of IFN-gamma in foam cell formation through upregulation of CXCL16/SR-PSOX. CXCR6 expression in the plaque confirms the presence of cells able to respond to CXCL16. Therefore, this chemokine/scavenger receptor could serve as a molecular link between lipid metabolism and immune activity in the atherosclerotic lesion.

  • 49.
    Wågsäter, Dick
    et al.
    Örebro University, Department of Clinical Medicine.
    Jatta, Ken
    Örebro University, Department of Clinical Medicine.
    Ocaya, Pauline
    Örebro University, Department of Clinical Medicine.
    Dimberg, Jan
    Sirsjö, Allan
    Örebro University, Department of Clinical Medicine.
    Expression of IL-1b, IL-1R1 I and IL-1Ra in human aortic smooth muscle cells: effects of all-trans retinoic acid2006Manuscript (preprint) (Other academic)
  • 50.
    Wågsäter, Dick
    et al.
    Örebro University, Department of Clinical Medicine.
    Jatta, Ken
    Örebro University, Department of Clinical Medicine.
    Ocaya, Pauline
    Örebro University, Department of Clinical Medicine.
    Dimberg, Jan
    Sirsjö, Allan
    Örebro University, Department of Clinical Medicine.
    Expression of IL-1β, IL-1 receptor type I and IL-1 receptor antagonist in human aortic smooth muscle cells: effects of all-trans-retinoic acid2006In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 43, no 4, p. 377-382Article in journal (Refereed)
    Abstract [en]

    The proinflammatory cytokine interleukin (IL)-1β and the IL-1 receptor antagonist are expressed by atherosclerotic plaques and may be linked to the development of atherosclerosis. Existing evidence shows that retinoids and their receptors are involved in inflammatory response and that they are found in atherosclerotic plaques. In all-trans-retinoic acid (atRA)-treated human aortic smooth muscle cells (AOSMC), significant increases in IL-1β levels were observed, compared with untreated cells. Examination of IL-1 receptor antagonist and IL-1 receptor type I levels did not show any difference between atRA-treated and -untreated AOSMC. The results show that atRA-treated AOSMC express both the precursor (33 kDa) and the active form (17 kDa) of the IL-1β protein. atRA-treated carotid lesions showed significantly elevated IL-1β mRNA levels (2.9 ± 2.33) compared with untreated lesions (2.0 ± 1.77; p < 0.05). These results support the role of atRA as a regulator of inflammation such as in atherosclerosis.

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