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  • 1.
    Biava, Pier M.
    et al.
    Scientific Institute of Research and Care Multimedica, Milano, Italy.
    Canaider, Silvia
    Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Unit of Histology, Embryology and Applied Biology, University of Bologna, Bologna, Italy; National Institute of Biostructures and Biosystems, Bologna, Italy.
    Facchin, Federica
    Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Unit of Histology, Embryology and Applied Biology, University of Bologna, Bologna, Italy; National Institute of Biostructures and Biosystems, Bologna, Italy.
    Bianconi, Eva
    Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Unit of Histology, Embryology and Applied Biology, University of Bologna, Bologna, Italy; National Institute of Biostructures and Biosystems, Bologna, Italy.
    Ljungberg, Liza
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Rotilio, Domenico
    Department of Haematology, Ospedali Riuniti BMM, Reggio Calabria, Italy.
    Burigana, Fabio
    Associazione Medicina e Complessità (AMEC), Trieste, Italy.
    Ventura, Carlo
    Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Unit of Histology, Embryology and Applied Biology, University of Bologna, Bologna, Italy; National Institute of Biostructures and Biosystems, Bologna, Italy; Stem Wave Institute for Tissue Healing (SWITH), Gruppo Villa Maria (GVM) Care & Research - Ettore Sansavini Health Science Foundation, Lugo (Ravenna), Italy.
    Stem Cell Differentiation Stage Factors from Zebrafish Embryo: A Novel Strategy to Modulate the Fate of Normal and Pathological Human (Stem) Cells2015In: Current Pharmaceutical Biotechnology, ISSN 1389-2010, E-ISSN 1873-4316, Vol. 16, no 9, p. 782-792Article, review/survey (Refereed)
    Abstract [en]

    In spite of the growing body of evidence on the biology of the Zebrafish embryo and stem cells, including the use of Stem Cell Differentiation Stage Factors (SCDSFs) taken from Zebrafish embryo to impact cancer cell dynamics, comparatively little is known about the possibility to use these factors to modulate the homeostasis of normal human stem cells or to modulate the behavior of cells involved in different pathological conditions. In the present review we recall in a synthetic way the most important researches about the use of SCDSFs in reprogramming cancer cells and in modulating the high speed of multiplication of keratinocytes which is characteristic of some pathological diseases like psoriasis. Moreover we add here the results about the capability of SCDSFs in modulating the homeostasis of human adipose-derived stem cells (hASCs) isolated from a fat tissue obtained with a novel-non enzymatic method and device. In addition we report the data not yet published about a first protein analysis of the SCDSFs and about their role in a pathological condition like neurodegeneration.

  • 2.
    Björck, Hanna M.
    et al.
    Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
    Eriksson, Per
    Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska, Institute, Stockholm, Sweden.
    Alehagen, Urban
    Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
    De Basso, Rachel
    Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
    Ljungberg, Liza U.
    Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
    Persson, Karin
    Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
    Dahlström, Ulf
    Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
    Länne, Toste
    Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
    Gender-specific association of the plasminogen activator inhibitor-1 4G/5G polymorphism with central arterial blood pressure2011In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 24, no 7, p. 802-8Article in journal (Refereed)
    Abstract [en]

    Background: The functional plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism has previously been associated with hypertension. In recent years, central blood pressure, rather than brachial has been argued a better measure of cardiovascular damage and clinical outcome. The aim of this study was to investigate the possible influence of the 4G/5G polymorphism on central arterial blood pressure in a cohort of elderly individuals.

    Methods: We studied 410 individuals, 216 men and 194 women, aged 70-88. Central pressures and pulse waveforms were calculated from the radial artery pressure waveform by the use of the SphygmoCor system and a generalized transfer function. Brachial pressure was recorded using oscillometric technique (Dinamap, Critikon, Tampa, FL). PAI-1 antigen was determined in plasma.

    Results: The results showed that central pressures were higher in women carrying the PAI-1 4G/4G genotype compared to female carriers of the 5G/5G genotype, (P = 0.025, P = 0.002, and P = 0.002 for central systolic-, diastolic-, and mean arterial pressure, respectively). The association remained after adjustment for potentially confounding factors related to hypertension. No association of the PAI-1 genotype with blood pressure was found in men. Multiple regression analysis revealed an association between PAI-1 genotype and plasma PAI-1 levels (P = 0.048).

    Conclusions: Our findings show a gender-specific association of the PAI-1 4G/5G polymorphism with central arterial blood pressure. The genotype effect was independent of other risk factors related to hypertension, suggesting that impaired fibrinolytic potential may play an important role in the development of central hypertension in women.

  • 3. Canaider, S.
    et al.
    Maioli, M.
    Facchin, F.
    Bianconi, E.
    Santaniello, S.
    Pigliaru, G.
    Ljungberg, Liza U.
    Burigana, F.
    Bianchi, F.
    Olivi, E.
    Tremolada, C.
    Biava, P.M.
    Ventura, C.
    Human Stem Cell Exposure to Developmental Stage Zebrafish Extracts: a Novel Strategy for Tuning Stemness and Senescence Patterning2014In: Cell, ISSN 2329-7042, Vol. 2, no 5, article id e1226Article in journal (Refereed)
    Abstract [en]

    Background: Zebrafish exhibits extraordinary ability for tissue regeneration. Despite growing investigations dissecting the molecular underpinning of such regenerative potential, little is known about the possibility to use the chemical inventory of the zebrafishembryo to modulate human stem cell dynamics.

    Methods: Extracts from zebrafish embryo were collected at different developmental stages, referred to as ZF1, ZF2, ZF3 (early stages), and ZF4, ZF5 (late stages). Human adipose-derived stem cells (hASCs), isolated from microfractured fat tissue obtained with a novel non-enzymatic method (Lipogems), were cultured in absence or presence of each developmental stage extract. Cell viability was assessed by MTT assay. Nuclear morphology was investigated by cell-permeable dye 4’,6-DAPI. Caspase-3 activity was assessed by ELISA. Gene transcription was monitored by real-time PCR.

    Results: Late developmental stage extracts decreased cell viability and elicited caspase-3 mediated apoptosis. This effect did not involve Bax or Bcl-2 transcription. Conversely, early developmental stage ZF1 did not affect cell viability or apoptosis, albeit increasing Bax/Bcl-2mRNA ratio. ZF1 enhanced transcription of the stemness/pluripotency genes Oct-4, Sox-2and c-Myc. ZF1 also induced the transcription of TERT, encoding the catalytic subunit of telomerase, as well as the gene expression of Bmi-1, a chromatin remodeler acting as a major telomerase-independent repressor of senescence. These transcriptional responses were restricted to the action of early stage factors, since they were not elicited by late developmental stage ZF5.

    Conclusions: Exposure to early developmental stage zebrafish embryo extracts may enhance stem cell expression of multipotency and activate both telomerase-dependent and -independent antagonists of cell senescence. These outcomes may prove rewarding during prolonged expansion in culture, as it occurs in most cell therapy protocols.

  • 4.
    Donner, Lili
    et al.
    Department of Clinical and Experimental Hemostasis, Hemotherapy and Transfusion Medicine, Heinrich Heine University, Düsseldorf, Germany.
    Fälker, Knut
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre, Örebro University Hospital, Örebro, Sweden.
    Gremer, Lothar
    Institute of Physical Biology, Heinrich Heine University, Düsseldorf, Germany; Institute of Structural Biochemistry (ICS-6), Research Centre Jülich, Jülich, Germany.
    Klinker, Stefan
    Institute of Physical Biology, Heinrich Heine University, Düsseldorf, Germany.
    Pagani, Giulia
    Institute for Pharmaceutical and Medicinal Chemistry, Department of Mathematics and Natural Sciences, Heinrich Heine University, Düsseldorf, Germany.
    Ljungberg, Liza U.
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre, Örebro University Hospital, Örebro, Sweden.
    Lothmann, Kimberley
    Institute of Physical Biology, Heinrich Heine University, Düsseldorf, Germany.
    Rizzi, Federica
    Department of Biomedical, Biotechnological, and Translation Sciences, University of Parma, Parma, Italy; Centre for Molecular and Translational Oncology (COMT), University of Parma, Parma, Italy; National Institute of Biostructure and Biosystems (INBB), Rome, Italy.
    Schaller, Martin
    Department of Dermatology, University of Tübingen, Tübingen, Germany.
    Gohlke, Holger
    Institute for Pharmaceutical and Medicinal Chemistry, Department of Mathematics and Natural Sciences, Heinrich Heine University, Düsseldorf, Germany.
    Willbold, Dieter
    Institute of Physical Biology, Heinrich Heine University, Düsseldorf, Germany; Institute of Structural Biochemistry (ICS-6), Research Centre Jülich, Jülich, Germany.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre, Örebro University Hospital, Örebro, Sweden.
    Elvers, Margitta
    Department of Clinical and Experimental Hemostasis, Hemotherapy and Transfusion Medicine, Heinrich Heine University, Düsseldorf, Germany.
    Platelets contribute to amyloid-β aggregation in cerebral vessels through integrin αIIbβ3-induced outside-in signaling and clusterin release2016In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 9, no 429, article id ra52Article in journal (Refereed)
    Abstract [en]

    Cerebral amyloid angiopathy (CAA) is a vascular dysfunction disorder characterized by deposits of amyloid-β (Aβ) in the walls of cerebral vessels. CAA and Aβ deposition in the brain parenchyma contribute to dementia and Alzheimer's disease (AD). We investigated the contribution of platelets, which accumulate at vascular Aβ deposits, to CAA. We found that synthetic monomeric Aβ40 bound through its RHDS (Arg-His-Asp-Ser) sequence to integrin αIIbβ3, which is the receptor for the extracellular matrix protein fibrinogen, and stimulated the secretion of adenosine diphosphate (ADP) and the chaperone protein clusterin from platelets. Clusterin promoted the formation of fibrillar Aβ aggregates, and ADP acted through its receptors P2Y1 and P2Y12 on platelets to enhance integrin αIIbβ3 activation, further increasing the secretion of clusterin and Aβ40 binding to platelets. Platelets from patients with Glanzmann's thrombasthenia, a bleeding disorder in which platelets have little or dysfunctional αIIbβ3, indicated that the abundance of this integrin dictated Aβ-induced clusterin release and platelet-induced Aβ aggregation. The antiplatelet agent clopidogrel, which irreversibly inhibits P2Y12, inhibited Aβ aggregation in platelet cultures; in transgenic AD model mice, this drug reduced the amount of clusterin in the circulation and the incidence of CAA. Our findings indicate that activated platelets directly contribute to CAA by promoting the formation of Aβ aggregates and that Aβ, in turn, activates platelets, creating a feed-forward loop. Thus, antiplatelet therapy may alleviate fibril formation in cerebral vessels of AD patients.

  • 5.
    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.

  • 6.
    Hayderi, A.
    et al.
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Sirsjö, A.
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Salihovic, S.
    Örebro University, School of Medical Sciences. Inflammatory Response and Infection Susceptibility Centre.
    Ljungberg, L.
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Interferon gamma reprograms glutamine metabolic pathways in human aortic smooth muscle cells2023In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 379, no Suppl. 1, p. S8-S8, article id P024Article in journal (Other academic)
    Abstract [en]

    Background and Aims: Cells within atherosclerotic lesions have a higher glutamine demand than cells in healthy vessel although glutaminase, the enzyme converting glutamine to glutamate, is significantly downregulated in human carotid lesions. This may suggest rewiring of glutamine metabolic pathways in atherosclerotic lesions, caused by infiltrating immune cells and or their cytokines. Here we aimed at exploring the enzymes and transporters involved in glutamine metabolism in human carotid atherosclerotic tissues and aortic smooth muscle cells (hAoSMCs) exposed to interferon gamma.

    Methods: Protein and mRNA from interferon gamma-treated hAoSMCs were subjected to Western blot or qRT-PCR for quantification of enzymes and transporters involved in glutamine metabolism. H2DCFDA probe was utilized for detection of intracellular reactive oxygen species (ROS) using flow cytometry. The expression of these enzymes and transporters was also evaluated in human carotid lesions (GEO accession: GSE43292).

    Results: Interferon-treated hAoSMCs display a significantly lower expression of glutaminase followed by an increase in the expression of glutamine transporters, glutamine synthetase and glutamine-fructose-6-phosphate transaminase-1 (GFPT1). The level of ROS and the expression of enzymes involved in de novo synthesis of glutathione are elevated in interferon-treated cells. A similar expression pattern for these genes, expect for GFPT1, is also evident in human carotid lesions where glutaminase mRNA shows a strong positive correlation with SMC markers and a strong negative correlation with macrophage markers.

    Conclusions: Glutamine metabolism is disrupted in human carotid lesions and interferon gamma alters glutamine metabolism in hAoSMCs, which may favor the production of UDP-GlcNAc and reactive oxygen species.

  • 7.
    Hayderi, Assim
    et al.
    Örebro University, School of Medical Sciences.
    Ljungberg, Liza
    Örebro University, School of Medical Sciences.
    Kumawat, Ashok Kumar
    Örebro University, School of Medical Sciences.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences.
    Function of viperin in human aortic SMCS and its relevance for atherosclerosis2021In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 331, p. E88-E88Article in journal (Other academic)
    Abstract [en]

    Background and Aims: During atherosclerosis, activated vascular cells secrete chemokines to recruit leukocytes to the subendothelial space. Activated leukocytes, in particular activated T lymphocytes express IFN-γ, which affects the expression of numerous genes, including the antiviral protein viperin, in vascular cells. Viperin is expressed in endothelial cells of human carotid plaques but its relevance for vascular physiology and/or pathophysiology has not been established (Olofsson et al., 2005). We aimed at studying the function of viperin in human AoSMCs.

    Methods: Immunostaining of human carotid plaques was performed to determine the expression and localization of viperin in carotid plaques. To study the role of viperin in regulation of vascular inflammation, viperin was silenced using siRNA in cultured human AoSMCs, prior to stimulation with IFN-γ. Release of inflammatory mediators was analyzed using OLINK proteomics and ELISA, and the gene expression was analyzed by qRT-PCR.

    Results: Viperin is expressed in endothelial cells, macrophages and smooth muscle cells in human carotid plaques. OLINK data analysis revealed reduction in release of CCL3, CXCL9, CXCL10 and CXCL11 by AoSMCs that were targeted with anti-viperin siRNA prior to stimulation with IFN-γ. Using ELISA and qRT-PCR, we could confirm the reduction of IFN-γ-induced CXCL10 and CXCL11 in viperin knockdown AoSMCs.

    Conclusions: Viperin is expressed in human carotid plaques and seem to be involved in regulating the expression of CXCL10 and CXCL11 in AoSMCs. Thus, it may play a role in recruitment of T lymphocytes to the subendothelial space in atherosclerotic plaques.

  • 8.
    Kardeby, Caroline
    et al.
    Örebro University, School of Medical Sciences.
    Fälker, Knut
    Örebro University, School of Medical Sciences.
    Haining, Elizabeth J.
    Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
    Criel, Maarten
    Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
    Lindkvist, Madelene
    Örebro University, School of Medical Sciences.
    Barroso, Ruben
    Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, The Midlands, United Kingdom.
    Påhlsson, Peter
    Division of Cell Biology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Ljungberg, Liza
    Örebro University, School of Medical Sciences.
    Tengdelius, Mattias
    Division of Organic Chemistry, Linköping University, Linköping, Sweden.
    Rainger, G. Ed.
    Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
    Watson, Stephanie
    Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
    Eble, Johannes A.
    Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Münster, Germany.
    Hoylaerts, Marc F.
    Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
    Emsley, Jonas
    Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, The Midlands, United Kingdom; Division of Biomolecular Science and Medicinal Chemistry, Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
    Konradsson, Peter
    Division of Organic Chemistry, Linköping University, Linköping, Sweden.
    Watson, Steve P.
    Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, The Midlands, United Kingdom.
    Sun, Yi
    Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, The Midlands, United Kingdom.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences.
    Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα2019In: Blood Advances, ISSN 2473-9529 , E-ISSN 2473-9537, Vol. 3, no 3, p. 275-287Article in journal (Refereed)
    Abstract [en]

    Fucoidans are sulfated fucose-based polysaccharides that activate platelets and have pro- and anticoagulant effects; thus, they may have therapeutic value. In the present study, we show that 2 synthetic sulfated α-l-fucoside-pendant glycopolymers (with average monomeric units of 13 and 329) and natural fucoidans activate human platelets through a Src- and phosphatidylinositol 3-kinase (PI3K)-dependent and Syk-independent signaling cascade downstream of the platelet endothelial aggregation receptor 1 (PEAR1). Synthetic glycopolymers and natural fucoidan stimulate marked phosphorylation of PEAR1 and Akt, but not Syk. Platelet aggregation and Akt phosphorylation induced by natural fucoidan and synthetic glycopolymers are blocked by a monoclonal antibody to PEAR1. Direct binding of sulfated glycopolymers to epidermal like growth factor (EGF)-like repeat 13 of PEAR1 was shown by avidity-based extracellular protein interaction screen technology. In contrast, synthetic glycopolymers and natural fucoidans activate mouse platelets through a Src- and Syk-dependent pathway regulated by C-type lectin-like receptor 2 (CLEC-2) with only a minor role for PEAR1. Mouse platelets lacking the extracellular domain of GPIbα and human platelets treated with GPIbα-blocking antibodies display a reduced aggregation response to synthetic glycopolymers. We found that synthetic sulfated glycopolymers bind directly to GPIbα, substantiating that GPIbα facilitates the interaction of synthetic glycopolymers with CLEC-2 or PEAR1. Our results establish PEAR1 as the major signaling receptor for natural fucose-based polysaccharides and synthetic glycopolymers in human, but not in mouse, platelets. Sulfated α-l-fucoside-pendant glycopolymers are unique tools for further investigation of the physiological role of PEAR1 in platelets and beyond.

  • 9.
    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)
  • 10.
    Kumawat, Ashok Kumar
    et al.
    Örebro University, School of Medical Sciences.
    Zegeye, Mulugeta M
    Örebro University, School of Medical Sciences.
    Paramel Varghese, Geena
    Örebro University, School of Medical Sciences.
    Baumgartner, Roland
    Division of Cardiovascular Medicine, Department of Medicine, Solna, Centre for Molecular Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Gisterå, Anton
    Division of Cardiovascular Medicine, Department of Medicine, Solna, Centre for Molecular Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Amegavie, Obed
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Hellberg, Sanna
    Division of Cardiovascular Medicine, Department of Medicine, Solna, Centre for Molecular Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Jin, Hong
    Division of Cardiovascular Medicine, Department of Medicine, Solna, Centre for Molecular Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Caravaca, April S.
    Division of Cardiovascular Medicine, Department of Medicine, Solna, Centre for Molecular Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Söderström, Leif Å.
    Division of Cardiovascular Medicine, Department of Medicine, Solna, Centre for Molecular Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Gudmundsdotter, Lindvi
    Frejd, Fredrik Y.
    Affibody AB, Solna, Sweden.
    Ljungberg, Liza
    Örebro University, School of Medical Sciences.
    Olofsson, Peder S.
    Division of Cardiovascular Medicine, Department of Medicine, Solna, Centre for Molecular Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Ketelhuth, Daniel F. J.
    Division of Cardiovascular Medicine, Department of Medicine, Solna, Centre for Molecular Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences.
    Inhibition of IL17A Using an Affibody Molecule Attenuates Inflammation in ApoE-Deficient Mice2022In: Frontiers in Cardiovascular Medicine, E-ISSN 2297-055X, Vol. 9, article id 831039Article in journal (Refereed)
    Abstract [en]

    The balance between pro- and anti-inflammatory cytokines released by immune and non-immune cells plays a decisive role in the progression of atherosclerosis. Interleukin (IL)-17A has been shown to accelerate atherosclerosis. In this study, we investigated the effect on pro-inflammatory mediators and atherosclerosis development of an Affibody molecule that targets IL17A. Affibody molecule neutralizing IL17A, or sham were administered in vitro to human aortic smooth muscle cells (HAoSMCs) and murine NIH/3T3 fibroblasts and in vivo to atherosclerosis-prone, hyperlipidaemic ApoE(-/-) mice. Levels of mediators of inflammation and development of atherosclerosis were compared between treatments. Exposure of human smooth muscle cells and murine NIH/3T3 fibroblasts in vitro to alpha IL-17A Affibody molecule markedly reduced IL6 and CXCL1 release in supernatants compared with sham exposure. Treatment of ApoE(-/-) mice with alpha IL-17A Affibody molecule significantly reduced plasma protein levels of CXCL1, CCL2, CCL3, HGF, PDGFB, MAP2K6, QDPR, and splenocyte mRNA levels of Ccxl1, Il6, and Ccl20 compared with sham exposure. There was no significant difference in atherosclerosis burden between the groups. In conclusion, administration of alpha IL17A Affibody molecule reduced levels of pro-inflammatory mediators and attenuated inflammation in ApoE(-/-) mice.

  • 11.
    Lindkvist, Madelene
    et al.
    Örebro University, School of Medical Sciences.
    Fernberg, Ulrika
    Örebro University, School of Medical Sciences.
    Ljungberg, Liza
    Örebro University, School of Medical Sciences.
    Fälker, Knut
    Örebro University, School of Medical Sciences.
    Fernström, Maria
    Örebro University, School of Health Sciences.
    Hurtig-Wennlöf, Anita
    Örebro University, School of Health Sciences.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences.
    Individual variations in platelet reactivity towards ADP, epinephrine, collagen and nitric oxide, and the association to arterial function in young, healthy adults2019In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 174, p. 5-12Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Platelet aggregation and secretion can be induced by a large number of endogenous activators, such as collagen, adenosine diphosphate (ADP) and epinephrine. Conversely, the blood vessel endothelium constitutively release platelet inhibitors including nitric oxide (NO) and prostacyclin. NO and prostacyclin are also well-known vasodilators and contribute to alterations in local blood flow and systemic blood pressure.

    MATERIALS AND METHODS: In this study we investigated individual variations in platelet reactivity and arterial functions including blood pressure and flow-mediated vasodilation (FMD) in 43 young, healthy individuals participating in the Lifestyle, Biomarkers and Atherosclerosis (LBA) study. Platelet aggregation and dense granule secretion were measured simultaneously by light transmission and luminescence. FMD was measured with ultrasound.

    RESULTS: The platelet function assay showed inter-individual differences in platelet reactivity. Specifically, a sub-group of individuals had platelets with an increased response to low concentrations of ADP and epinephrine, but not collagen. When the NO-donor S-nitroso-N-acetyl-DL-penicillamine (SNAP) was combined with high doses of these platelet activators, the results indicated for sub-groups of NO-sensitive and NO-insensitive platelets. The individuals with NO-sensitive platelets in response to SNAP in combination with collagen had a higher capacity of FMD of the arteria brachialis.

    CONCLUSIONS: Platelet reactivity towards ADP, epinephrine and NO differs between young, healthy individuals. Some individuals have a more effective response towards NO, both in the aspect of platelet inhibition ex vivo, as well as vasodilation in vivo.

  • 12.
    Lindkvist, Madelene
    et al.
    Örebro University, School of Medical Sciences.
    Ljungberg, Liza U
    Örebro University, School of Medical Sciences.
    Fälker, Knut
    Örebro University, School of Medical Sciences.
    Ramström, Sofia
    Örebro University, School of Medical Sciences.
    Kardeby, Caroline
    Örebro University, School of Medical Sciences.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences.
    IL-6 trans-signalling inhibits micro- and macro-aggregation induced by epinephrine in human plateletsManuscript (preprint) (Other academic)
  • 13.
    Lindkvist, Madelene
    et al.
    Örebro University, School of Medical Sciences.
    Zegeye, Mulugeta M
    Örebro University, School of Medical Sciences.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences.
    Ljungberg, Liza
    Örebro University, School of Medical Sciences.
    Pleiotropic, Unique and Shared Responses Elicited by IL-6 Family Cytokines in Human Vascular Endothelial Cells2022In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 3, article id 1448Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial cells express glycoprotein 130 (gp130), which is utilized as a signaling receptor by cytokines in the interleukin-6 (IL-6) family. Several IL-6 family cytokines can be found in the circulatory system during physiological or pathological conditions, and may influence endothelial function and response. This study evaluated and compared the cellular and molecular responses induced by IL-6 family cytokines in human endothelial cells. A proteomic analysis showed that IL-6 family cytokines induce the release of a range of proteins from endothelial cells, such as C-C motif chemokine ligand 23, hepatocyte growth factor, and IL-6. Pathway analysis indicated that gp130-signaling in endothelial cells regulates several functions related to angiogenesis and immune cell recruitment. The present investigation also disclosed differences and similarities between different IL-6 family cytokines in their ability to induce protein release and regulate gene expression and intracellular signaling, in regards to which oncostatin M showed the most pronounced effect. Further, this study showed that soluble gp130 preferentially blocks trans-signaling-induced responses, but does not affect responses induced by classic signaling. In conclusion, IL-6 family cytokines induce both specific and overlapping molecular responses in endothelial cells, and regulate genes and proteins involved in angiogenesis and immune cell recruitment.

  • 14.
    Lindkvist, Madelene
    et al.
    Örebro University, School of Medical Sciences.
    Zegeye, Mulugeta M
    Örebro University, School of Medical Sciences.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences.
    Ljungberg, Liza U
    Örebro University, School of Medical Sciences.
    Comparative evaluation of gp130 signalling cytokines in human endothelial cells: evidence for both specific and overlapping molecular responsesManuscript (preprint) (Other academic)
  • 15.
    Ljungberg, Liza U.
    et al.
    Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Alehagen, Urban
    Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    De Basso, Rachel
    ivision of Cardiovascular Medicine, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Persson, Karin
    Division of Drug Research, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Dahlström, Ulf
    Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Länne, Toste
    Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Circulating angiotensin-converting enzyme is associated with left ventricular dysfunction, but not with central aortic hemodynamics2013In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 166, no 2, p. 540-1Article in journal (Refereed)
  • 16.
    Ljungberg, Liza U.
    et al.
    Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Alehagen, Urban
    Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Länne, Toste
    Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Björck, Hanna
    Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    De Basso, Rachel
    Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Dahlström, Ulf
    Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Persson, Karin
    Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    The association between circulating angiotensin-converting enzyme and cardiovascular risk in the elderly: a cross-sectional study.2011In: jraas. Journal of the renin-angiotensin-aldosterone system, ISSN 1470-3203, E-ISSN 1752-8976, Vol. 12, no 3, p. 281-9Article in journal (Refereed)
    Abstract [en]

    Introduction: A polymorphism in the angiotensin-converting enzyme gene (ACE I/D polymorphism) has been associated with increased risk for cardiovascular disease (CVD). This polymorphism affects the level of circulating ACE, but there is great individual variation, even between those with the same genotype. Few previous studies have investigated the link between circulating ACE and cardiovascular risk. The aim of this study was to investigate this association, and to examine the relationship between ACE level, ACE genotype and CVD.

    Materials and methods: The study population consisted of 322 men and 350 women aged 69-87. Plasma ACE level was determined using enzyme-linked immunosorbent assay (ELISA), and ACE genotype was analysed using PCR followed by gel electrophoresis.

    Results: In men, ACE levels increased with increasing number of cardiovascular risk factors (p = 0.003). There was a significant association in men between increased ACE level and both diabetes (p = 0.007) and smoking (p = 0.037).

    Conclusions: This study shows that cardiovascular risk factors (such as smoking and diabetes) are associated with higher levels of circulating ACE in men. High ACE levels may represent one of the cellular mechanisms involved in producing the vascular damage associated with cardiovascular risk factors.

  • 17.
    Ljungberg, Liza U.
    et al.
    Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    De Basso, R.
    Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Alehagen, U.
    Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Björck, H. M.
    Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Persson, K.
    Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Dahlström, U.
    Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Länne, T.
    Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Impaired abdominal aortic wall integrity in elderly men carrying the angiotensin-converting enzyme D allele2011In: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 42, no 3, p. 309-16Article in journal (Refereed)
    Abstract [en]

    Objective: A polymorphism in the angiotensin-converting-enzyme gene (ACE I/D) has been associated with abdominal aortic aneurysm and a link between aortic aneurysm and aortic stiffness has been suggested. This study aimed to explore the links between ACE I/D polymorphism, circulating ACE and abdominal aortic wall integrity as reflected by abdominal aortic wall stiffness.

    Material: A total of 212 men and 194 women, aged 70-88 years, were studied.

    Methods: Mechanical properties of the abdominal aorta were determined using the Wall Track System, ACE genotype using the polymerase chain reaction (PCR) and circulating ACE level by enzyme-linked immunosorbent assay (ELISA).

    Results: In men, pulsatile diameter change differed between genotypes (II 0.70, ID 0.55 and DD 0.60 mm, P = 0.048), whereas a tendency was seen for distensibility coefficient (DC) (II 10.38, ID 7.68 and ID 8.79, P = 0.058). Using a dominant model (II vs. ID/DD), men carrying the ACE D allele had lower pulsatile diameter change (P = 0.014) and DC (P = 0.017) than II carriers. Multiple regression analyses showed additional associations between the D allele and increased stiffness β, and reduced compliance coefficient.

    Conclusion: Men carrying the ACE D allele have stiffer abdominal aortas compared with II carriers. Deranged abdominal aortic stiffness indicates impaired vessel wall integrity, which, along with other local predisposing factors, may be important in aneurysmal disease.

  • 18.
    Ljungberg, Liza U.
    et al.
    Division of Drug Research/Pharmacology, Department of Medical and Health Sciences, Linköping University, Linköping.
    Persson, Karin
    Division of Drug Research/Pharmacology, Department of Medical and Health Sciences, Linköping University, Linköping.
    Effect of nicotine and nicotine metabolites on angiotensin-converting enzyme in human endothelial cells2008In: Endothelium, ISSN 1062-3329, E-ISSN 1029-2373, Vol. 15, no 5-6, p. 239-45Article in journal (Refereed)
    Abstract [en]

    Nicotine has been shown to induce endothelial dysfunction, which is an early marker of atherosclerosis. Nicotine undergoes extensive metabolism in the liver, forming a number of major and minor metabolites. There are very limited data on the effect of nicotine metabolites on the cardiovascular system. This study investigates the effects of nicotine and the nicotine metabolites, cotinine, cotinine-N-oxide, nicotine-1'-N-oxide, norcotinine, trans-3'-hydroxycotinine, on angiotensin-converting enzyme (ACE) in human endothelial cells. Cultured endothelial cells obtained from human umbilical cord vein (HUVECs) were stimulated with nicotine or nicotine metabolites in concentrations similar to those observed in plasma during smoking. ACE activity and expression were analyzed using commercial kits. The results showed that nicotine and nicotine metabolites can increase both activity and expression of ACE. However, a marked individual variation in the response to the drugs was observed. This variation was not associated with the ACE insertion/deletion polymorphism. Tobacco contains numerous chemical compounds, and the underlying cause for development of atherosclerosis in smokers is probably multifactorial. The results from this study could explain one cellular mechanism by which smoking exerts negative effect on the vascular system.

  • 19.
    Ljungberg, Liza U.
    et al.
    Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Persson, Karin
    Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Eriksson, Andreas C
    Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Green, Henrik
    Faculty of Health Sciences, Linköping University, Linköping, Sweden; Science for Life Laboratory, School of Biotechnology, Division of Gene Technology, Royal Institute of Technology, Solna, Sweden.
    Whiss, Per A
    Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Effects of nicotine, its metabolites and tobacco extracts on human platelet function in vitro2013In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 27, no 2, p. 932-8Article in journal (Refereed)
    Abstract [en]

    Cigarette smoking is a leading cause of cardiovascular disease. The cardiovascular effects of smoking are probably multifactorial, including effects on platelets. Previous reports investigating the effects of nicotine and tobacco on platelet function are inconsistent. The present study investigated in vitro effects of nicotine, its major metabolites, tobacco extracts and extract of tobacco-free snuff on human platelets. None of the metabolites cotinine, cotinine-N-oxide, nicotine-1'-N-oxide or trans-3'-hydroxycotinine (0.1-10 μM) affected platelet aggregation or P-selectin expression. Nicotine (10 μM) weakly increased platelet aggregation, whereas trans-3'-hydroxycotinine (0.1 μM) and nicotine-1'-N-oxide (1-10 μM) weakly inhibited adhesion to fibrinogen. To elucidate the influence of other tobacco compounds, we investigated the impact of moist tobacco and smoke extracts on platelet function. Filtered extracts of oral snuff, cigarette smoke and tobacco free snuff inhibited platelet adhesion concentration-dependently. The inhibitory effects of tobacco extracts on platelet adhesion were independent of nicotine content and the nitric-oxide-pathway and not mediated through a platelet-nicotine-receptor. Taken together, tobacco extracts inhibit platelet activation during short-term in vitro challenge. As only limited effects of nicotine and nicotine metabolites were seen, the tobacco-induced platelet inhibition are likely induced by other compounds present in tobacco and tobacco free snuff.

  • 20.
    Ljungberg, Liza U.
    et al.
    Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Faculty of Health Science, Linköping University, Linköping, Sweden.
    Östgren, Carl Johan
    Primary Care, Department of Medical and Health Sciences, Faculty of Health Science, Linköping University, Linköping, Sweden.
    Nyström, Fredrik H.
    Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Faculty of Health Science, Linköping University, Linköping, Sweden.
    Länne, Toste
    Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Faculty of Health Science, Linköping University, Linköping, Sweden.
    Associations of genetic polymorphisms in the renin-angiotensin system with central aortic and ambulatory blood pressure in type 2 diabetic patients2014In: jraas. Journal of the renin-angiotensin-aldosterone system, ISSN 1470-3203, E-ISSN 1752-8976, Vol. 15, no 1, p. 61-8Article in journal (Refereed)
    Abstract [en]

    Patients with type 2 diabetes (T2D) are at high risk of developing hypertension and related cardiovascular disease. The renin-angiotensin system (RAS) plays a central role in regulation of blood pressure (BP). Accordingly, each component of this system represents a potential candidate in the etiology of hypertension. This study investigated the impact of polymorphisms within the RAS on ambulatory and central BP in T2D subjects. A cohort of 761 subjects (55-65 years) with T2D was studied. Ambulatory and central BP were measured, and ACE I/D genotype, angiotensinogen M235T, renin rs6693954 and ATR1-A1166C polymorphisms were analyzed. Women carrying the AA-genotype had lower 24-hour and day-time systolic and diastolic BP (p<0.05), and lower night-time and central diastolic BP (p<0.05), compared to T allele carriers. In men, the AA-genotype was instead associated with higher central diastolic BP (p=0.018) and higher augmentation index (p=0.016). Further, the associations between the renin rs6693954 SNP and diastolic BP were strongly gender dependent (p≤0.001). In T2D patients, there is a gender-dependent association of the renin rs6693954 SNP with central and ambulatory BP. Women carrying the renin rs6693954 AA-genotype may be protected against the higher BP seen in men with the same genotype.

  • 21.
    Ljungberg, Liza
    et al.
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre.
    Zegeye, Mulugeta M
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre.
    Kardeby, Caroline
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre.
    Fälker, Knut
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre.
    Global Transcriptional Profiling Reveals Novel Autocrine Functions of Interleukin 6 in Human Vascular Endothelial Cells2020In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, Vol. 2020, article id 4623107Article in journal (Refereed)
    Abstract [en]

    Background: Interleukin 6 (IL6) is a multifunctional cytokine produced by various cells, including vascular endothelial cells. IL6 has both pro- and non-/anti-inflammatory functions, and the response to IL6 is dependent on whether it acts via the membrane-bound IL6 receptor alpha (IL6R alpha) (classic signaling) or the soluble form of the receptor (transsignaling). As human endothelial cells produce IL6 and at the same time express IL6R alpha, we hypothesized that IL6 may have autocrine functions.

    Methods: Knockdown of IL6 in cultured human endothelial cells was performed using siRNA. Knockdown efficiency was evaluated using ELISA. RNA sequencing was employed to characterize the transcriptional consequence of IL6 knockdown, and Ingenuity Pathway Analysis was used to further explore the functional roles of IL6.

    Results: Knockdown of IL6 in cultured endothelial cells resulted in a 84-92% reduction in the release of IL6. Knockdown of IL6 resulted in dramatic changes in transcriptional pattern; knockdown of IL6 in the absence of soluble IL6R alpha (sIL6R alpha) led to differential regulation of 1915 genes, and knockdown of IL6 in the presence of sIL6R alpha led to differential regulation of 1967 genes (fold change 1.5, false discovery rate<0.05). Pathway analysis revealed that the autocrine functions of IL6 in human endothelial cells are mainly related to basal cellular functions such as regulation of cell cycle, signaling, and cellular movement. Furthermore, we found that knockdown of IL6 activates functions related to adhesion, binding, and interaction of endothelial cells, which seem to be mediated mainly via STAT3.

    Conclusion: In this study, a large number of novel genes that are under autocrine regulation by IL6 in human endothelial cells were identified. Overall, our data indicate that IL6 acts in an autocrine manner to regulate basal cellular functions, such as cell cycle regulation, signaling, and cellular movement, and suggests that the autocrine functions of IL6 in human endothelial cells are mediated via IL6 classic signaling.

  • 22.
    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)
  • 23.
    Paramel Varghese, Geena
    et al.
    Örebro University, School of Medical Sciences.
    Karadimou, Glykeria
    Laboratory of Immunobiology, Center for Bioelectronic Medicine, Department of Medicine, Karolinska Institute, Solna, Stockholm, Sweden.
    Göthlin Eremo, Anna
    Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory.
    Ljungberg, Liza
    Örebro University, School of Medical Sciences.
    Hedin, Ulf
    Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Olofsson, Peder S.
    Laboratory of Immunobiology, Center for Bioelectronic Medicine, Department of Medicine, Karolinska Institute, Solna, Stockholm, Sweden; Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA.
    Folkersen, Lasse
    Institute of Biological Psychiatry, Sankt Hans Hospital, Copenhagen, Denmark.
    Paulsson Berne, Gabrielle
    Laboratory of Immunobiology, Center for Bioelectronic Medicine, Department of Medicine, Karolinska Institute, Solna, Stockholm, Sweden.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences.
    Fransén, Karin
    Örebro University, School of Medical Sciences.
    Expression of CARD8 in human atherosclerosis and its regulation of inflammatory proteins in human endothelial cells2020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 19108Article in journal (Refereed)
    Abstract [en]

    The Caspase activation and recruitment domain 8 (CARD8) protein is a component of innate immunity and overexpression of CARD8 mRNA was previously identified in atherosclerosis. However, very little is known about the regulation of CARD8 in endothelial cells and atherosclerosis. The aim of this study was to investigate CARD8 in the regulation of cytokine and chemokine expression in endothelial cells. Sections of human atherosclerotic lesions and non-atherosclerotic arteries were immunostained for CARD8 protein. Expression of CARD8 was correlated to mediators of inflammation in atherosclerotic lesions using Biobank of Karolinska Endarterectomies microarray data. The CARD8 mRNA was knocked-down in human umbilical vein endothelial cells (HUVECs) in vitro, followed by quantitative RT-PCR analysis and OLINK Proteomics. Endothelial and smooth muscle cells in arterial tissue expressed CARD8 and CARD8 correlated with vWF, CD163 and the expression of inflammatory genes, such as CXCL1, CXCL6 and PDGF-A in plaque. Knock-down of CARD8 in HUVECs significantly altered proteins involved in inflammatory response, such as CXCL1, CXCL6, PDGF-A, MCP-1 and IL-6. The present study suggest that CARD8 regulate the expression of cytokines and chemokines in endothelial cells and atherosclerotic lesions, suggesting that CARD8 plays a significant role in endothelial activation.

  • 24.
    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)
  • 25.
    Zegeye, M.
    et al.
    Örebro University, School of Medical Sciences.
    Ljungberg, L.
    Örebro University, School of Medical Sciences.
    Nakka, S.
    Department Of Microbiology And Immunology, University of Gothenburg, Gothenburg, Sweden.
    Andersson, J.
    Department Of Public Health And Clinical Medicine, Skellefteå Research Unit, Umeå University, Skellefteå, Sweden.
    Söderberg, S.
    Department Of Public Health And Clinical Medicine, Medicine Unit, Umeå University, Umeå, Sweden.
    Kumawat, A.
    Örebro University, School of Medical Sciences.
    Sirsjö, A.
    Örebro University, School of Medical Sciences.
    Soluble LDL-receptor is induced by TNF-Α and inhibits hepatocytic clearance of LDL-cholesterol2023In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 379, no Suppl. 1, p. S61-S61, article id P195Article in journal (Other academic)
    Abstract [en]

    Background and Aims: LDL-c is cleared from the circulation mainly by hepatic LDL-receptor mediated endocytosis. Defective LDL-c clearance and hence its elevation in circulation is one of the risk factors for myocardial infarction (MI). A soluble LDL-R (sLDL-R) exists in human plasma and exhibits strong correlation with circulating LDL-c and conditions that promote chronic inflammation. However, the mechanistic interplay between sLDL-R, inflammation and MI remains to be investigated.

    Methods: In vitro studies using HepG2 cells treated with TNF-α, and a nested case-control study was conducted to investigate the relationship between plasma sLDL-R, TNF-α and risk of future MI.

    Results: Stimulation of HepG2 cells with TNF-α induces release of sLDL-R with limited effect on surface expression of LDL-R. TNF-α induces gene expression of peptidases ADAM17 and MMP14 in HepG2 cells, and inhibition of ADAM17 and MMP-14 significantly reduces the TNF-α induced sLDL-R release. Although TNF-α treatment of HepG2 cells has limited effect on LDL-c endocytosis, HepG2 cells incubated with recombinant sLDL-R showed reduced LDL-c uptake in a dose-dependent manner. In a nested case-control study, baseline sLDL-R in plasma was positively correlated with plasma total cholesterol level. Further, a 2-fold increase in plasma sLDL-R was associated with 2.1x higher risk of future MI. Using mediation analyses, we determined that significant proportion of the association is mediated by elevation in plasma cholesterol level.

    Conclusions: Our study suggests that sLDL-R is generated by TNF-α via membrane shedding. Further, an increase in sLDL-R could inhibit hepatic clearance of LDL-c increasing its half-life in the circulation and contributing to the pathogenesis of MI.

  • 26.
    Zegeye, Mulugeta M.
    et al.
    Örebro University, School of Medical Sciences.
    Andersson, Blanka
    Department of Biomedical and Clinical Sciences (BKV), Division of Inflammation and Infection (II), Linköping University Campus US, Linköping, Sweden.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences.
    Ljungberg, Liza U.
    Örebro University, School of Medical Sciences.
    IL-6 trans-Signaling Impairs Sprouting Angiogenesis by Inhibiting Migration, Proliferation and Tube Formation of Human Endothelial Cells.2020In: Cells, E-ISSN 2073-4409, Vol. 9, no 6, article id 1414Article in journal (Refereed)
    Abstract [en]

    Sprouting angiogenesis is the formation of new capillaries from existing vessels in response to tissue hypoxia due to growth/development, repair/healing, and also chronic inflammation. In this study, we aimed to elucidate the effect of IL-6, a pleiotropic cytokine with both pro-inflammatory and anti-inflammatory functions, in regulating the sprouting angiogenic response of endothelial cells (ECs). We found that activation of IL-6 trans-signaling inhibited the migration, proliferation, and tube formation ability of ECs. In addition, inhibition of the autocrine IL-6 classic-signaling by depleting endogenous IL-6 from ECs impaired their tube formation ability. At the molecular level, we found that IL-6 trans-signaling in ECs upregulated established endogenous anti-angiogenic factors such as CXCL10 and SERPINF1 while at the same time downregulated known endogenous pro-angiogenic factors such as cKIT and CXCL8. Furthermore, prior activation of ECs by IL-6 trans-signaling alters their response to vascular endothelial growth factor-A (VEGF-A), causing an increased p38, but decreased Erk1/2 phosphorylation. Collectively, our data demonstrated the dual facets of IL-6 in regulating the sprouting angiogenic function of ECs. In addition, we shed light on molecular mechanisms behind the IL-6 trans-signaling mediated impairment of endothelial sprouting angiogenic response.

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    IL-6 trans-Signaling Impairs Sprouting Angiogenesis by Inhibiting Migration, Proliferation and Tube Formation of Human Endothelial Cells
  • 27.
    Zegeye, Mulugeta M
    et al.
    Örebro University, School of Medical Sciences.
    Andersson, Jonas S. O.
    Skellefteå Research Unit, Department of Public Health and Clinical Medicine, Umeå University, Sweden.
    Wennberg, Patrik
    Department of Public Health and Clinical Medicine, Family Medicine, Umeå University, Sweden.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences.
    Ljungberg, Liza
    Örebro University, School of Medical Sciences.
    IL-6 as a Mediator of the Association Between Traditional Risk Factors and Future Myocardial Infarction: A Nested Case-Control Study2021In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 41, no 4, p. 1570-1579Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Studies elucidating the importance of IL (interleukin)-6 trans-signaling associated with risk of future myocardial infarction (MI) are scarce. Additionally, whether elevation in IL-6 explains part of the association between traditional risk factors and future MI has not been explored.

    Approach and Results: We conducted a nested case-control study including a total of 584 participants (292 cases and 292 controls) from Västerbotten Intervention Programme and MONICA (Multinational Monitoring of Trends and Determinants in Cardiovascular Disease) cohorts. At baseline, plasma cholesterol levels were measured, and clinical characteristics of participants were collected. In this study, we measured the plasma concentration of IL-6, sIL-6R (soluble IL-6 receptor), and sgp130 (soluble-gp130). To estimate extent of IL-6 trans-signaling, we estimated plasma concentration of a novel biomarker, the IL-6 binary complex. IL-6 binary complex concentration was significantly elevated in participants who experienced MI compared with those who did not. Univariate analyses showed that a 2-fold increase in IL-6 binary complex was associated with 2.45× higher risk of future MI (95% CI relative risk, 1.65-3.66, P<0.001). Receiver operating characteristics analyses revealed that the predictive performance of IL-6 binary complex (area under the curve, 0.614) was equivalent to that of IL-6 (area under the curve, 0.603). Furthermore, using Process mediation analyses tool, we found statistically significant indirect effect of smoking and hypertension on future MI that is mediated through increased IL-6 binary complex or plasma IL-6.

    CONCLUSIONS: IL-6 and IL-6 binary complex concentration in plasma were significantly associated with future MI. Our data additionally imply that both the elevated plasma IL-6, and the IL-6 binary complex concentration could partly explain, and, thus, might hypothetically be functionally associated with the increased risk of MI in smokers and hypertensive participants.

  • 28.
    Zegeye, Mulugeta M
    et al.
    Örebro University, School of Medical Sciences.
    Andersson, Jonas SO
    Department of Public Health and Clinical Medicine, Skellefteå Research Unit, Umeå University, Skellefteå, Sweden, Sweden.
    Wennberg, Patrik
    Department of Public Health and Clinical Medicine, Family Medicine, Umeå University, Sweden.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences.
    Ljungberg, Liza
    Örebro University, School of Medical Sciences.
    Interleukin-6 as a mediator of the association between traditional risk factors and future Myocardial Infarction: A nested case-control studyManuscript (preprint) (Other academic)
  • 29.
    Zegeye, Mulugeta M
    et al.
    Örebro University, School of Medical Sciences.
    Kumawat, Ashok K
    Örebro University, School of Medical Sciences.
    Matic, Ljubica
    Karolinska Institute, Stockholm, Sweden.
    Lengquist, Mariette
    Karolinska Institute, Stockholm, Sweden.
    Hayderi, Assim
    Örebro University, School of Medical Sciences.
    Hedin, Ulf
    Karolinska Institute, Stockholm, Sweden.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences.
    Ljungberg, Liza U
    Örebro University, School of Medical Sciences.
    IL-6 trans-signaling regulates vascular endothelial laminin profile and inflammatory responses: possible mechanism for immune cell recruitment during atherosclerosis?Manuscript (preprint) (Other academic)
  • 30.
    Zegeye, Mulugeta M
    et al.
    Örebro University, School of Medical Sciences.
    Kumawat, Ashok Kumar
    Örebro University, School of Medical Sciences.
    Matic, L.
    Karolinska Institutet Vascular Surgery Division, Department of Molecular Medicine and Surgery, Stockholm, Sweden.
    Lengquist, M.
    Karolinska Institutet Vascular Surgery Division, Department of Molecular Medicine and Surgery, Stockholm, Sweden.
    Hyderi, A.
    Örebro University, School of Medical Sciences, Örebro, Sweden.
    Hedin, U.
    Karolinska Institutet Vascular Surgery Division, Department of Molecular Medicine and Surgery, Stockholm, Sweden.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences.
    Ljungberg, Liza
    Örebro University, School of Medical Sciences.
    IL-6 trans-signaling regulates vascular endothelial laminin profile and inflammatory responses: Possible mechanism for immune cell recruitment during atherosclerosis?2021In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 331, p. E61-E61Article in journal (Other academic)
    Abstract [en]

    Background and Aims: We aimed to investigate the role of IL-6 trans-signaling in regulating the release of endothelial inflammatory mediators and endothelial basement mebrane proteins, laminins. We also aimed to investigate the laminin composition in atherosclerotic plaques in relation to the immune cell content.

    Methods: HUVECs were cultured for in vitro experiments. The BiKE cohort was used to assess expression of laminins in atherosclerotic plaques and healthy vessels. Gene and protein expression was analysed using Microarray/qPCR and proximity extension assay, immunostaining or immunoblotting techniques respectively.

    Results: The release of 20 inflammatory proteins from ECs was significantly altered (3 downregulated, 17 upregulated) in response to stimulation with IL-6 and sIL-6R (p-value <0.05, FDR 5%). Ingenuity pathway analyses predicted that these proteins enhance lymphocyte binding and transmigration while inhibiting transmigration of granulocytes. ECs treated with combination of IL-6 and sIL-6R upregulated expression of LAMA5 while downregulating LAMA4. Transcriptomic and proteomic analyses showed that both endothelial LAMA4 and LAMA5 were significantly lower in atherosclerotic plaques compared to healthy vessels. In addition, expression of endothelial LAMA5 was significantly lower in plaques from symptomatic patients compared to those from asymptomatic patients. We also showed that endothelial laminins are negatively correlated with immune cell markers.

    Conclusions: Our findings suggest that IL-6 trans-signaling regulates endothelial inflammatory proteins and laminin production that enhance binding and trans-migration of lymphocytes. In the context of atherosclerosis, expression of laminin alpha chains is altered and also appeared to be associated with plaque stability. Our data also revealed a relationship between laminin chains and immune cell content in atherosclerotic plaques.

  • 31.
    Zegeye, Mulugeta M.
    et al.
    Örebro University, School of Medical Sciences.
    Lindkvist, Madelene
    Örebro University, School of Medical Sciences.
    Fälker, Knut
    Örebro University, School of Medical Sciences.
    Kumawat, Ashok K.
    Örebro University, School of Medical Sciences.
    Paramel Varghese, Geena
    Örebro University, School of Medical Sciences. Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Dalhousie Medicine New Brunswick, Saint John, Canada.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences.
    Ljungberg, Liza U.
    Örebro University, School of Medical Sciences.
    Activation of the JAK/STAT3 and PI3K/AKT pathways are crucial for IL-6 trans-signaling-mediated pro-inflammatory response in human vascular endothelial cells2018In: Cell Communication and Signaling, E-ISSN 1478-811X, Vol. 16, no 1, article id 55Article in journal (Refereed)
    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.

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    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
  • 32.
    Zegeye, Mulugeta M
    et al.
    Örebro University, School of Medical Sciences.
    Matic, Ljubica
    Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
    Lengquist, Mariette
    Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
    Hayderi, Assim
    Örebro University, School of Medical Sciences.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences.
    Hedin, Ulf
    Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences.
    Ljungberg, Liza U.
    Örebro University, School of Medical Sciences.
    Kumawat, Ashok Kumar
    Örebro University, School of Medical Sciences.
    Interleukin-6 trans-signaling induced laminin switch contributes to reduced trans-endothelial migration of granulocytic cells2023In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 371, p. 41-53Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: Laminins are essential components of the endothelial basement membrane, which predominantly contains LN421 and LN521 isoforms. Regulation of laminin expression under pathophysiological conditions is largely unknown. In this study, we aimed to investigate the role of IL-6 in regulating endothelial laminin profile and characterize the impact of altered laminin composition on the phenotype, inflammatory response, and function of endothelial cells (ECs).

    METHODS: HUVECs and HAECs were used for in vitro experiments. Trans-well migration experiments were performed using leukocytes isolated from peripheral blood of healthy donors. The BiKE cohort was used to assess expression of laminins in atherosclerotic plaques and healthy vessels. Gene and protein expression was analyzed using Microarray/qPCR and proximity extension assay, ELISA, immunostaining or immunoblotting techniques, respectively.

    RESULTS: Stimulation of ECs with IL-6+sIL-6R, but not IL-6 alone, reduces expression of laminin α4 (LAMA4) and increases laminin α5 (LAMA5) expression at the mRNA and protein levels. In addition, IL-6+sIL-6R stimulation of ECs differentially regulates the release of several proteins including CXCL8 and CXCL10, which collectively were predicted to inhibit granulocyte transmigration. Experimentally, we demonstrated that granulocyte migration is inhibited across ECs pre-treated with IL-6+sIL-6R. In addition, granulocyte migration across ECs cultured on LN521 was significantly lower compared to LN421. In human atherosclerotic plaques, expression of endothelial LAMA4 and LAMA5 is significantly lower compared to control vessels. Moreover, LAMA5-to-LAMA4 expression ratio was negatively correlated with granulocytic cell markers (CD177 and myeloperoxidase (MPO)) and positively correlated with T-lymphocyte marker CD3.

    CONCLUSIONS: We showed that expression of endothelial laminin alpha chains is regulated by IL-6 trans-signaling and contributes to inhibition of trans-endothelial migration of granulocytic cells. Further, expression of laminin alpha chains is altered in human atherosclerotic plaques and is related to intra-plaque abundance of leukocyte subpopulations.

  • 33.
    Zegeye, Mulugeta M
    et al.
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre.
    Nakka, Sravya S.
    Department of Infectious Diseases, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden.
    Andersson, Jonas S. O.
    Department of Public Health and Clinical Medicine, Skellefteå Research Unit, Umeå University, 931 86, Skellefteå, Sweden.
    Söderberg, Stefan
    Department of Public Health and Clinical Medicine, Medicine Unit, Umeå University, Umeå, Sweden.
    Ljungberg, Liza
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre.
    Kumawat, Ashok Kumar
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre.
    Soluble LDL-receptor is induced by TNF-α and inhibits hepatocytic clearance of LDL-cholesterol2023In: Journal of Molecular Medicine, ISSN 0946-2716, E-ISSN 1432-1440, Vol. 101, no 12, p. 1615-1626Article in journal (Refereed)
    Abstract [en]

    Defective LDL-C clearance and hence its elevation in the circulation is an established risk factor for cardiovascular diseases (CVDs) such as myocardial infarction (MI). A soluble LDL-receptor (sLDL-R) has been detected in human plasma which correlates strongly with circulating LDL-C and classical conditions that promote chronic inflammation. However, the mechanistic interplay between sLDL-R, inflammation, and CVDs remains to be investigated. Here, we report that stimulation of HepG2 cells with TNF-α induces the release of sLDL-R into culture supernatants. In addition, TNF-α induces gene expression of peptidases ADAM-17 and MMP-14 in HepG2 cells, and inhibiting these peptidases using TMI 1 significantly reduces the TNF-α induced sLDL-R release. We found that a soluble form of recombinant LDL-R (100 nM) can strongly bind to LDL-C and form a stable complex (KD = E-12). Moreover, incubation of HepG2 cells with this recombinant LDL-R resulted in reduced LDL-C uptake in a dose-dependent manner. In a nested case-control study, we found that baseline sLDL-R in plasma is positively correlated with plasma total cholesterol level. Furthermore, a twofold increase in plasma sLDL-R was associated with a 55% increase in the risk of future MI [AOR = 1.55 (95% CI = 1.10-2.18)]. Nevertheless, mediation analyses revealed that a significant proportion of the association is mediated by elevation in plasma cholesterol level (indirect effect β = 0.21 (95% CI = 0.07-0.38). Collectively, our study shows that sLDL-R is induced by a pro-inflammatory cytokine TNF-α via membrane shedding. Furthermore, an increase in sLDL-R could inhibit hepatic clearance of LDL-C increasing its half-life in the circulation and contributing to the pathogenesis of MI. KEY MESSAGES: TNF-α causes shedding of hepatocytic LDL-R through induction of ADAM-17 and MMP-14. sLDL-R binds strongly to LDL-C and inhibits its uptake by hepatocytic cells. Plasma sLDL-R is positively correlated with TNF-α and cholesterol. Plasma sLDL-R is an independent predictor of myocardial infarction (MI). Plasma cholesterol mediates the association between sLDL-R and MI.

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