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  • 1.
    Biswas, Dipsikha
    et al.
    Dalhousie Med New Brunswick, St John, NB, Canada.
    Cowie, Andrew
    Dalhousie Med New Brunswick, St John, NB, Canada.
    Tozer, Kathleen
    Dalhousie Med New Brunswick, St John, NB, Canada.
    Perez, Lester J.
    Dalhousie Med New Brunswick, St John, NB, Canada.
    Trivedi, Purvi
    Dalhousie Med New Brunswick, St John, NB, Canada.
    Bartlett, Jordan J.
    Dalhousie Med New Brunswick, St John, NB, Canada.
    Duffley, Luke
    Univ New Brunswick, St John, NB, Canada.
    Dao, Khoi Thien
    Univ New Brunswick, St John, NB, Canada.
    Paramel Varghese, Geena
    Dalhousie Med New Brunswick, St John, NB, Canada..
    Aguiar, Christie
    St Johns Hosp, St John, NB, Canada.
    Yip, Alexandra M.
    St Johns Hosp, St John, NB, Canada.
    Shea, Jennifer
    St Johns Hosp, St John, NB, Canada.
    Brunt, Keith
    Dalhousie Med New Brunswick, St John, NB, Canada.
    Legare, Jean-Francois
    St Johns Hosp, St John, NB, Canada.
    Hassan, Ansar
    St Johns Hosp, St John, NB, Canada.
    Kienesberger, Petra
    Dalhousie Med New Brunswick, St John, NB, Canada.
    Pulinilkunnil, Thomas
    Dalhousie Med New Brunswick, St John, NB, Canada.
    Adverse Cardiometabolic Outcomes in Obese Patients Correlates Strongly with Defective Branched-Chain Amino Acid Catabolism2018Inngår i: Journal of Molecular and Cellular Cardiology, ISSN 0022-2828, E-ISSN 1095-8584, Vol. 124, s. 121-122Artikkel i tidsskrift (Annet vitenskapelig)
    Fulltekst (pdf)
    sammanfattning
  • 2.
    D'Souza, K.
    et al.
    Dalhousie Medicine New Brunswick, United States.
    Nzirorera, C.
    Dalhousie Medicine New Brunswick, United States.
    Cowie, A.M.
    Dalhousie Medicine New Brunswick, United States.
    Paramel Varghese, Geena
    Dalhousie Medicine New Brunswick, United States.
    Trivedi, P.
    Dalhousie Medicine New Brunswick, United States.
    Eichmann, T.O.
    Department of Biochemistry and Molecular Biology, Dalhousie University, Institute of Molecular Biosciences, Saint John, Canada.
    Biswas, D.
    Dalhousie Medicine New Brunswick, United States.
    Touaibia, M.
    University of Graz, Center for Explorative Lipidomics, BioTechMed-Graz, Department of Chemistry and Biochemistry, Graz, Austria.
    Morris, A.J.
    Dalhousie Medicine New Brunswick, United States; Université de Moncton, Division of Cardiovascular Medicine, Moncton, Canada.
    Aidinis, V.
    University of Kentucky, Lexington Veterans Affairs Medical Center, Division of Immunology, Lexington, United States.
    Kane, D.A.
    Biomedical Sciences Research Center “Alexander Fleming”, Department of Human Kinetics, Athens, Greece.
    Pulinilkunnil, T.
    Dalhousie Medicine New Brunswick, United States.
    Kienesberger, P.C.
    Dalhousie Medicine New Brunswick, United States.
    Autotaxin-Lysophosphatidic Acid Signaling Contributed to Obesity-Induced Insulin Resistance in Muscle and Impairs Mitochondrial Metabolism2018Inngår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 59, nr 10, s. 1805-1817Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Autotaxin (ATX) is an adipokine that generates the bioactive lipid, lysophosphatidic acid (LPA). ATX-LPA signaling has been implicated in diet-induced obesity and systemic insulin resistance. However, it remains unclear whether the ATX-LPA pathway influences insulin function and energy metabolism in target tissues, particularly skeletal muscle, the major site of insulin-stimulated glucose disposal. The objective of this study was to test whether the ATX-LPA pathway impacts tissue insulin signaling and mitochondrial metabolism in skeletal muscle during obesity. Male mice with heterozygous ATX deficiency (ATX +/-) were protected from obesity, systemic insulin resistance, and cardiomyocyte dysfunction following high-fat high-sucrose (HFHS) feeding. HFHS-fed ATX +/- mice also had improved insulin-stimulated AKT phosphorylation in white adipose tissue, liver, heart, and skeletal muscle. Preserved insulin-stimulated glucose transport in muscle from HFHS fed ATX +/- mice was associated with improved mitochondrial pyruvate oxidation in the absence of changes in fat oxidation and ectopic lipid accumulation. Similarly, incubation with LPA decreased insulin-stimulated AKT phosphorylation and mitochondrial energy metabolism in C2C12 myotubes at baseline and following palmitate-induced insulin resistance. Taken together, our results suggest that the ATX-LPA pathway contributes to obesity-induced insulin resistance in metabolically relevant tissues. Our data also suggest that LPA directly impairs skeletal muscle insulin signaling and mitochondrial function. Preserved insulin-stimulated glucose transport in muscle from HFHS fed ATX +/- mice was associated with improved mitochondrial pyruvate oxidation in the absence of changes in fat oxidation and ectopic lipid accumulation. Similarly, incubation with LPA decreased insulin-stimulated AKT phosphorylation and mitochondrial energy metabolism in C2C12 myotubes at baseline and following palmitate-induced insulin resistance. Taken together, our results suggest that the ATX-LPA pathway contributes to obesity-induced insulin resistance in metabolically relevant tissues. Our data also suggest that LPA directly impairs skeletal muscle insulin signaling and mitochondrial function. Preserved insulin-stimulated glucose transport in muscle from HFHS fed ATX +/- mice was associated with improved mitochondrial pyruvate oxidation in the absence of changes in fat oxidation and ectopic lipid accumulation. Similarly, incubation with LPA decreased insulin-stimulated AKT phosphorylation and mitochondrial energy metabolism in C2C12 myotubes at baseline and following palmitate-induced insulin resistance. Taken together, our results suggest that the ATX-LPA pathway contributes to obesity-induced insulin resistance in metabolically relevant tissues. Our data also suggest that LPA directly impairs skeletal muscle insulin signaling and mitochondrial function. incubation with LPA decreased insulin-stimulated AKT phosphorylation and mitochondrial energy metabolism in C2C12 myotubes at baseline and following palmitate-induced insulin resistance. Taken together, our results suggest that the ATX-LPA pathway contributes to obesity-induced insulin resistance in metabolically relevant tissues. Our data also suggest that LPA directly impairs skeletal muscle insulin signaling and mitochondrial function. incubation with LPA decreased insulin-stimulated AKT phosphorylation and mitochondrial energy metabolism in C2C12 myotubes at baseline and following palmitate-induced insulin resistance. Taken together, our results suggest that the ATX-LPA pathway contributes to obesity-induced insulin resistance in metabolically relevant tissues. Our data also suggest that LPA directly impairs skeletal muscle insulin signaling and mitochondrial function.

    Fulltekst (pdf)
    Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolism
  • 3.
    Kardeby, Caroline
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper. Cardiovascular Research Centre (CVRC).
    Paramel Varghese, Geena
    Örebro universitet, Institutionen för medicinska vetenskaper. 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 universitet, Institutionen för medicinska vetenskaper. Cardiovascular Research Centre (CVRC).
    Koufaki, Maria
    National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
    Fransén, Karin
    Örebro universitet, Institutionen för medicinska vetenskaper. Cardiovascular Research Centre (CVRC).
    Grenegård, Magnus
    Örebro universitet, Institutionen för medicinska vetenskaper. Cardiovascular Research Centre (CVRC).
    A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibitionManuskript (preprint) (Annet vitenskapelig)
  • 4.
    Kardeby, Caroline
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Paramel Varghese, Geena
    Örebro universitet, Institutionen för medicinska vetenskaper.
    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 universitet, Institutionen för medicinska vetenskaper.
    Koufaki, Maria
    National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
    Fransén, Karin
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Grenegård, Magnus
    Örebro universitet, Institutionen för medicinska vetenskaper.
    A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition2019Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 857, artikkel-id 172428Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 5.
    Paramel, Geena
    et al.
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    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 universitet, Institutionen för hälsovetenskap och medicin.
    Särndahl, Eva
    Örebro universitet, Institutionen för läkarutbildning.
    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 universitet, Institutionen för hälsovetenskap och medicin.
    Fransén, Karin
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    CARD8 gene encoding a protein of innate immunity is expressed in human atherosclerosis and associated with markers of inflammation2013Inngår i: Clinical Science, ISSN 0143-5221, E-ISSN 1470-8736, Vol. 125, nr 8, s. 401-407Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 6.
    Paramel, Geena
    et al.
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Fransén, Karin
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Hurtig-Wennlöf, Anita
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Bengtsson, Torbjörn
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Jansson, Jan-Håkan
    Department of Internal Medicine, Skellefteå Hospital and Umeå University Hospital.
    Sirsjö, Allan
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Q705K variant in NLRP3 gene confers protection against myocardial infarction in female individuals2013Inngår i: Biomedical Reports, ISSN 2049-9434, Vol. 1, nr 6, s. 879-882Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 7.
    Paramel, Geena
    et al.
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Sirsjö, Allan
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Fransén, Karin
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Role of genetic alterations in the NLRP3 and CARD8 genes in health and disease2015Inngår i: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, artikkel-id 846782Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 8.
    Paramel, Geena
    et al.
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Uporova, Ludmila
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Halfvarson, Jonas
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Sirsjö, Allan
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Fransén, Karin
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Polymorphism in the NLRP3 inflammasome-associated EIF2AK2 gene and inflammatory bowel disease2015Inngår i: Molecular Medicine Reports, ISSN 1791-2997, E-ISSN 1791-3004, Vol. 11, nr 6, s. 4579-4584Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 9.
    Paramel Varghese, Geena
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Innate immunity in human atherosclerosis and myocardial infarction: Role of CARD8 and NLRP32017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Atherosclerosis is complex inflammatory disease of the arterial wall with progressive accumulation of lipids and narrowing of the vessel. Increasing evidence suggest that inflammation plays an important role in plaque stability and often accelerate cardiovascular events such as myocardial infarction (MI). Among the vast number of inflammatory cytokines, IL-1β is known to be a key modulator in vessel wall inflammation and acceleration of the atherosclerotic process. The biologically active IL-1β is regulated by a multiprotein complex known as the NLRP3 inflammasome complex. In this thesis, we have focused on polymorphisms in the NLRP3 and CARD8 genes and their possible association to atherosclerosis and/or MI. We have also investigated the expression of inflammasome components NLRP3 and CARD8 in atherosclerosis and the role of genetic variants for the expression of these genes. The expression of NLRP3, CARD8, ASC, caspase-1, IL-1β, and IL-18 were found significantly upregulated in atherosclerotic lesions compared to normal arteries. Human carotid plaques not only express the NLRP3 inflammasome, but also release IL-1β upon exposure to lipopolysaccharide (LPS), adenosine triphosphate (ATP) and cholesterol crystals, which suggest NLRP3 inflammasome activation in human atherosclerotic lesions. Also, CARD8 was found to be important in the regulation of several inflammatory markers in endothelial cells, like RANTES, IP10 and ICAM-1. We further assessed the potential association of a CARD8 polymorphism and polymorphisms located downstream of the NLRP3 gene to the risk of MI in two independent Swedish cohorts. The CARD8 variant exhibited no association to risk of MI in either of the two cohorts. Some of the minor alleles of NLRP3 variants were associated with increased IL-1β levels and to NLRP3 mRNA levels in peripheral blood monocytic cells (PBMC). Taken together, the present thesis shows that NLRP3 inflammasome activation and increased expression of CARD8 in the atherosclerotic plaque might be possible contributors to the enhanced inflammatory response and leukocyte infiltration in the pathophysiology of atherosclerosis.

    Delarbeid
    1. NLRP3 Inflammasome Expression and Activation in Human Atherosclerosis
    Åpne denne publikasjonen i ny fane eller vindu >>NLRP3 Inflammasome Expression and Activation in Human Atherosclerosis
    Vise andre…
    2016 (engelsk)Inngår i: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 5, nr 5, artikkel-id e003031Artikkel i tidsskrift (Fagfellevurdert) Published
    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.

    sted, utgiver, år, opplag, sider
    Hoboken, USA: Wiley-Blackwell Publishing Inc., 2016
    Emneord
    Inflammasome, interleukin-1b, myocardial infarction, NLRP3, polymorphism
    HSV kategori
    Forskningsprogram
    Kardiologi
    Identifikatorer
    urn:nbn:se:oru:diva-50441 (URN)10.1161/JAHA.115.003031 (DOI)000386711200020 ()27207962 (PubMedID)
    Forskningsfinansiär
    Swedish Research Council, 6816 K2012-64X-12233-13-3Swedish Heart Lung Foundation, 20110359Magnus Bergvall Foundation
    Merknad

    Funding Agencies:

    Center of Excellence for Research on Inflammation and Cardiovascular Disease (CERIC) Linnaeus Center8703

    Foundation for Strategic Research, Uppdrag Besegra Stroke P581/2011-123

    Strategic Cardiovascular Programs of Karolinska Institutet, Stockholm County Council ALF 20110279

    Örebro University

    Sigurd and Elsa Goljes Foundation

    Tilgjengelig fra: 2016-05-26 Laget: 2016-05-26 Sist oppdatert: 2018-09-12bibliografisk kontrollert
    2. Q705K variant in NLRP3 gene confers protection against myocardial infarction in female individuals
    Åpne denne publikasjonen i ny fane eller vindu >>Q705K variant in NLRP3 gene confers protection against myocardial infarction in female individuals
    Vise andre…
    2013 (engelsk)Inngår i: Biomedical Reports, ISSN 2049-9434, Vol. 1, nr 6, s. 879-882Artikkel i tidsskrift (Fagfellevurdert) Published
    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.

    HSV kategori
    Identifikatorer
    urn:nbn:se:oru:diva-35448 (URN)10.3892/br.2013.155 (DOI)
    Tilgjengelig fra: 2014-06-19 Laget: 2014-06-19 Sist oppdatert: 2017-10-18bibliografisk kontrollert
    3. CARD8 gene encoding a protein of innate immunity is expressed in human atherosclerosis and associated with markers of inflammation
    Åpne denne publikasjonen i ny fane eller vindu >>CARD8 gene encoding a protein of innate immunity is expressed in human atherosclerosis and associated with markers of inflammation
    Vise andre…
    2013 (engelsk)Inngår i: Clinical Science, ISSN 0143-5221, E-ISSN 1470-8736, Vol. 125, nr 8, s. 401-407Artikkel i tidsskrift (Fagfellevurdert) Published
    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.

    sted, utgiver, år, opplag, sider
    London, United Kingdom: Portland Press, 2013
    Emneord
    Caspase activation and recruitment domain 8 (CARD8), cytokines, gene polymorphism, inflammasome, myocardial infarction, rs2043211
    HSV kategori
    Forskningsprogram
    Medicin
    Identifikatorer
    urn:nbn:se:oru:diva-30985 (URN)10.1042/CS20120572 (DOI)000323852600009 ()23611467 (PubMedID)2-s2.0-84880141884 (Scopus ID)
    Forskningsfinansiär
    Swedish Heart Lung FoundationSwedish Research Council, 521-2009-4203 349-2007-8703
    Merknad

    Funding Agencies:

    Magnus Bergvalls Foundation

    Örebro University

    Tilgjengelig fra: 2013-09-27 Laget: 2013-09-27 Sist oppdatert: 2018-08-27bibliografisk kontrollert
    4. CARD8, a protein of innate immunity regulates the release of inflammatory cytokines in human endothelial cells
    Åpne denne publikasjonen i ny fane eller vindu >>CARD8, a protein of innate immunity regulates the release of inflammatory cytokines in human endothelial cells
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Forskningsprogram
    Biomedicin
    Identifikatorer
    urn:nbn:se:oru:diva-54142 (URN)
    Tilgjengelig fra: 2016-12-20 Laget: 2016-12-20 Sist oppdatert: 2018-01-13bibliografisk kontrollert
    Fulltekst (pdf)
    Innate immunity in human atherosclerosis and myocardial infarction
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  • 10.
    Paramel Varghese, Geena
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Dalhousie Medicine New Brunswick, Saint John, Canada.
    D’Souza, K.
    Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Dalhousie Medicine New Brunswick, Saint John, Canada.
    Kienesberger, P.
    Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Dalhousie Medicine New Brunswick, Saint John, Canada.
    Lysophosphatidic Acid Signaling in Obesity and Insulin Resistance2018Inngår i: Nutrients, ISSN 2072-6643, E-ISSN 2072-6643, Vol. 10, nr 4, artikkel-id 399Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Although simple in structure, lysophosphatidic acid (LPA) is a potent bioactive lipid that profoundly influences cellular signaling and function upon binding to G protein-coupled receptors (LPA1-6). The majority of circulating LPA is produced by the secreted enzyme autotaxin (ATX). Alterations in LPA signaling, in conjunction with changes in autotaxin (ATX) expression and activity, have been implicated in metabolic and inflammatory disorders including obesity, insulin resistance, and cardiovascular disease. This review summarizes our current understanding of the sources and metabolism of LPA with focus on the influence of diet on circulating LPA. Furthermore, we explore how the ATX-LPA pathway impacts obesity and obesity-associated disorders, including impaired glucose homeostasis, insulin resistance, and cardiovascular disease.

    Fulltekst (pdf)
    Lysophosphatidic Acid Signaling in Obesity and Insulin Resistance
  • 11.
    Paramel Varghese, Geena
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper.
    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 universitet, Institutionen för medicinska vetenskaper.
    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 universitet, Institutionen för medicinska vetenskaper.
    NLRP3 Inflammasome Expression and Activation in Human Atherosclerosis2016Inngår i: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 5, nr 5, artikkel-id e003031Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 12.
    Paramel Varghese, Geena
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Göthlin Eremo, Anna
    Örebro University Hospital, Örebro, Sweden.
    Ljungberg, Liza
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Sirsjö, Allan
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Fransén, Karin
    Örebro universitet, Institutionen för hälsovetenskaper.
    CARD8, a protein of innate immunity regulates the release of inflammatory cytokines in human endothelial cellsManuskript (preprint) (Annet vitenskapelig)
  • 13.
    Paramel Varghese, Geena
    et al.
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Zhang, Boxi
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Khalaf, Hazem
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Ljungberg, Liza U.
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Sirsjö, Allan
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Bengtsson, Torbjörn
    Örebro universitet, Institutionen för läkarutbildning.
    Fransén, Karin
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Poryphyromonas gingivalis induces IL-1β in aortic smooth muscle cells: possible role of gingipains?Manuskript (preprint) (Annet vitenskapelig)
  • 14.
    Zegeye, Mulugeta M.
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Lindkvist, Madelene
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Fälker, Knut
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Kumawat, Ashok K.
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Paramel Varghese, Geena
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Dalhousie Medicine New Brunswick, Saint John, Canada.
    Grenegård, Magnus
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Sirsjö, Allan
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Ljungberg, Liza U.
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Activation of the JAK/STAT3 and PI3K/AKT pathways are crucial for IL-6 trans-signaling-mediated pro-inflammatory response in human vascular endothelial cells2018Inngår i: Cell Communication and Signaling, ISSN 1478-811X, E-ISSN 1478-811X, Vol. 16, nr 1, artikkel-id 55Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: IL-6 classic signaling is linked to anti-inflammatory functions while the trans-signaling is associated with pro-inflammatory responses. Classic signaling is induced via membrane-bound IL-6 receptor (IL-6R) whereas trans-signaling requires prior binding of IL-6 to the soluble IL-6R. In both cases, association with the signal transducing gp130 receptor is compulsory. However, differences in the downstream signaling mechanisms of IL-6 classic- versus trans-signaling remains largely elusive.

    METHODS: In this study, we used flow cytometry, quantitative PCR, ELISA and immuno-blotting techniques to investigate IL-6 classic and trans-signaling mechanisms in Human Umbilical Vein Endothelial Cells (HUVECs).

    RESULTS: We show that both IL-6R and gp130 are expressed on the surface of human vascular endothelial cells, and that the expression is affected by pro-inflammatory stimuli. In contrast to IL-6 classic signaling, IL-6 trans-signaling induces the release of the pro-inflammatory chemokine Monocyte Chemoattractant Protein-1 (MCP-1) from human vascular endothelial cells. In addition, we reveal that the classic signaling induces activation of the JAK/STAT3 pathway while trans-signaling also activates the PI3K/AKT and the MEK/ERK pathways. Furthermore, we demonstrate that MCP-1 induction by IL-6 trans-signaling requires simultaneous activation of the JAK/STAT3 and PI3K/AKT pathways.

    CONCLUSIONS: Collectively, our study reports molecular differences in IL-6 classic- and trans-signaling in human vascular endothelial cells; and elucidates the pathways which mediate MCP-1 induction by IL-6 trans-signaling.

    Fulltekst (pdf)
    Activation of the JAK/STAT3 and PI3K/AKT pathways are crucial for IL-6 trans-signaling-mediated pro-inflammatory response in human vascular endothelial cells
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