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    Reduced degradation of the chemokine MCP-3 by matrix metalloproteinase-2 exacerbates myocardial inflammation in experimental viral cardiomyopathy (2011)

    Art
    Zeitschriftenartikel / wissenschaftlicher Beitrag
    Autoren
    Westermann, Dirk
    Savvatis, Kostantinos
    Lindner, Diana
    Zietsch, Christin
    Becher, Peter Moritz
    Hammer, Elke
    Heimesaat, Markus M
    Bereswill, Stefan
    Völker, Uwe
    Escher, Felicitas
    Riad, Alexander
    Plendl, Johanna (WE 1)
    Klingel, Karin
    Poller, Wolfgang
    Schultheiss, Heinz-Peter
    Tschöpe, Carsten
    Quelle
    Circulation; 124(19) — S. 2082–93
    ISSN: 0009-7322
    Sprache
    Englisch
    Verweise
    DOI: 10.1161/CIRCULATIONAHA.111.035964
    Pubmed: 21986287
    Kontakt
    Institut für Veterinär-Anatomie

    Koserstr. 20
    14195 Berlin
    +49 30 838 53555
    anatomie@vetmed.fu-berlin.de

    Abstract / Zusammenfassung

    Myocarditis is an important cause for cardiac failure, especially in younger patients, followed by the development of cardiac dysfunction and death. The present study investigated whether gene deletion of matrix metalloproteinase-2 influences cardiac inflammation and function in murine coxsackievirus B3 (CVB3)-induced myocarditis.

    Matrix metalloproteinase-2 knockout mice (MMP-2(-/-)) and their wild-type controls (WT) were infected with CVB3 to induce myocarditis. Three days after infection, an increased invasion of CD4(+)-activated T cells into the myocardium was documented, followed by an excess of inflammatory cells 7 days after infection, which was significantly higher in the MMP-2(-/-)animals compared with the WT animals. Moreover, cardiac apoptosis, remodeling, viral load, and function were deteriorated in MMP-2(-/-) animals after CVB3 infection. This overwhelming inflammation was followed by 100% mortality after 15 days. This was associated with increased levels of MCP-3 in the cardiac tissue of MMP-2(-/-) mice. Because MMP-2 cleaves the chemokine MCP-3, the loss of this cleavage lead to an overreaction of the immune system with pronounced myocardial damage mediated by the inflammatory cells. When a neutralizing antibody against MCP-3 was given to MMP-2(-/-) mice, this exaggerated reaction of the immune system could be normalized to levels similar to WT-CVB3 animals.

    Loss of MMP-2 increased the inflammatory response after CVB3 infection, which impaired cardiac function and survival during CVB3-induced myocarditis. Matrix metalloproteinase-2-mediated chemokine cleavage has an important role in cardiac inflammation as a negative feedback mechanism.