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Adiponectin protects against Toll-like receptor 4-mediated cardiac inflammation and injury

Jenke, Alexander ; Wilk, Sabrina ; Poller, Wolfgang ; Eriksson, Urs ; Valaperti, Alan ; Rauch, Bernhard Hermann ; Stroux, Andrea ; Liu, Peter ; Schultheiss, Heinz-Peter ; Scheibenbogen, Carmen ; Skurk, Carsten

In: Cardiovascular Research, 2013, vol. 99, no. 3, p. 422-431

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    Titel
    • Adiponectin protects against Toll-like receptor 4-mediated cardiac inflammation and injury
    Autor
    • Jenke, Alexander. Department of Cardiology and Pneumology, Charité University Medicine Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, Berlin 12200, Germany
    • Wilk, Sabrina. Institute of Medical Immunology, Charité University Medicine Berlin, Campus Virchow-Klinikum, Augustenburger Platz, Berlin 13353, Germany
    • Poller, Wolfgang. Department of Cardiology and Pneumology, Charité University Medicine Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, Berlin 12200, Germany
    • Eriksson, Urs. Division of Cardioimmunology, Cardiovascular Research, Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, Winterthurerstrasse 190, Zurich 8057, Switzerland
    • Valaperti, Alan. Division of Cardiology, University of Toronto, 200 Elisabeth Street, Toronto, Ontario M5G 2C4, Canada
    • Rauch, Bernhard Hermann. Institute of Pharmacology, Ernst Moritz Arndt University of Greifswald, Felix-Hausdorff-Straße 3, Greifswald 17487, Germany
    • Stroux, Andrea. Institute of Medical Biometrics and Clinical Epidemiology, Charité University Medicine Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, Berlin 12200, Germany
    • Liu, Peter. Division of Cardiology, University of Toronto, 200 Elisabeth Street, Toronto, Ontario M5G 2C4, Canada
    • Schultheiss, Heinz-Peter. Department of Cardiology and Pneumology, Charité University Medicine Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, Berlin 12200, Germany
    • Scheibenbogen, Carmen. Institute of Medical Immunology, Charité University Medicine Berlin, Campus Virchow-Klinikum, Augustenburger Platz, Berlin 13353, Germany
    • Skurk, Carsten. Department of Cardiology and Pneumology, Charité University Medicine Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, Berlin 12200, Germany
    Dokumententyp
    • Postprint
    Sprache
    • Englisch
    Veröffentlicht in
    • Cardiovascular Research, 2013, vol. 99, no. 3, p. 422-431. Oxford University Press
    Andere elektronische Ausgabe
    OAI-PMH-ID
    • oai:doc.rero.ch:300454
    Summary
    Aims Adiponectin (APN) is an immunomodulatory and cardioprotective adipocytokine. Toll-like receptor (TLR) 4 mediates autoimmune reactions that cause myocarditis resulting in inflammation-induced cardiac injury. Here, we investigated whether APN inhibits inflammation and injury in autoimmune myocarditis by interfering with TLR4 signalling. Methods and results APN overexpression in murine experimental autoimmune myocarditis (EAM) down-regulated cardiac expression of TLR4 and its downstream targets tumour necrosis factor (TNF)α, interleukin (IL)-6, IL-12, CC chemokine ligand (CCL)2, and intercellular adhesion molecule (ICAM)-1 resulting in reduced infiltration with cluster of differentiation (CD)3+, CD14+, and CD45+ immune cells as well as diminished myocardial apoptosis. Expression of TLR4 signalling pathway components was unchanged in hearts and spleens of APN-knockout (APN-KO) mice. In vitro APN had no effect on TLR4 expression in cardiac and immune cells but induced dissociation of APN receptors from the activated TLR4/CD14 signalling complex. APN inhibited the expression of a TLR4-mediated inflammatory phenotype induced by exogenous and endogenous TLR4 ligands as assessed by attenuated nuclear factor (NF)-κB activation and reduced expression of TNFα, IL-6, CCL2, and ICAM-1. Accordingly, following TLR4 ligation, splenocytes from APN-KO mice showed enhanced expression of TNFα, IL-6, IL-12, CCL2, and ICAM-1, whereas dendritic cells (DCs) from APN-KO mice demonstrated increased activation and T-cell priming capacity. Moreover, APN diminished TLR4-mediated splenocyte migration towards cardiac cells as well as cardiomyocyte apoptosis after co-cultivation with splenocytes. Mechanistically, APN inhibited TLR4 signalling through cyclooxygenase (COX)-2, protein kinase A (PKA), and meiosis-specific serine/threonine kinase (MEK)1. Conclusion Our observations indicate that APN protects against inflammation and injury in autoimmune myocarditis by diminishing TLR4 signalling thereby attenuating inflammatory activation and interaction of cardiac and immune cells