Publikationsdatenbank

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

Bandzählung: 124

Heftzählung: 19

Seiten: 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.