title: Reduced degradation of the chemokine MCP-3 by matrix metalloproteinase-2 exacerbates myocardial inflammation in experimental viral cardiomyopathy.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Cardiology and Pneumology, Charité, Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, Berlin, Germany. dirk.westermann@web.de
authors: Dirk
authors: D
authors: Westermann
authors: Kostantinos
authors: K
authors: Savvatis
authors: Diana
authors: D
authors: Lindner
authors: Christin
authors: C
authors: Zietsch
authors: Peter Moritz
authors: PM
authors: Becher
authors: Elke
authors: E
authors: Hammer
authors: Markus M
authors: MM
authors: Heimesaat
authors: Stefan
authors: S
authors: Bereswill
authors: Uwe
authors: U
authors: Völker
authors: Felicitas
authors: F
authors: Escher
authors: Alexander
authors: A
authors: Riad
authors: Johanna
authors: J
authors: Plendl
authors: Karin
authors: K
authors: Klingel
authors: Wolfgang
authors: W
authors: Poller
authors: Heinz-Peter
authors: HP
authors: Schultheiss
authors: Carsten
authors: C
authors: Tschöpe
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology; D009202:Cardiomyopathies / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D054410:Chemokine CCL7 / Q000276:immunology / Q000378:metabolism*; D003384:Coxsackievirus Infections / Q000150:complications / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D029822:Enterovirus B, Human / Q000276:immunology*; D005109:Extracellular Matrix / Q000276:immunology / Q000378:metabolism; D025461:Feedback, Physiological / Q000502:physiology; D005260:Female; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009205:Myocarditis / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology / Q000821:virology; D061251:Primary Cell Culture; D012720:Severity of Illness Index
chemical_list: D057134:Antibodies, Neutralizing; C515451:Ccl7 protein, mouse; D054410:Chemokine CCL7; D016207:Cytokines; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse