Reduced Degradation of the Chemokine MCP-3 by Matrix Metalloproteinase-2 Exacerbates Myocardial Inflammation in Experimental Viral Cardiomyopathy
- 8 November 2011
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation
- Vol. 124 (19), 2082-2093
- https://doi.org/10.1161/circulationaha.111.035964
Abstract
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.Keywords
This publication has 37 references indexed in Scilit:
- RACK1 promotes Bax oligomerization and dissociates the interaction of Bax and Bcl-XLCellular Signalling, 2010
- Understanding the role of the extracellular matrix in cardiovascular development and disease: Where do we go from here?Journal of Molecular and Cellular Cardiology, 2010
- Tumor Necrosis Factor-α Promotes Myocarditis in Female Mice Infected with Coxsackievirus B3 Through Upregulation of CD1d on Hematopoietic CellsViral Immunology, 2010
- Gene Deletion of the Kinin Receptor B1 Attenuates Cardiac Inflammation and Fibrosis During the Development of Experimental Diabetic CardiomyopathyDiabetes, 2009
- Inflammation as a therapeutic target in heart failure? A scientific statement from the Translational Research Committee of the Heart Failure Association of the European Society of CardiologyEuropean Journal of Heart Failure, 2009
- Acute viral myocarditisEuropean Heart Journal, 2008
- Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sitesJCI Insight, 2007
- Reduced myocarditis following Coxsackievirus infection in cellular FLICE inhibitory protein – long form‐transgenic miceImmunology, 2006
- Inhibition of Urokinase-Type Plasminogen Activator or Matrix Metalloproteinases Prevents Cardiac Injury and Dysfunction During Viral MyocarditisCirculation, 2006
- Loss or Inhibition of uPA or MMP-9 Attenuates LV Remodeling and Dysfunction after Acute Pressure Overload in MiceThe American Journal of Pathology, 2005