title: Critical role of monocyte chemoattractant protein-1/CC chemokine ligand 2 in the pathogenesis of ischemic cardiomyopathy.
abstract: BACKGROUND
  Cardiac interstitial fibrosis plays an important role in the pathogenesis of ischemic cardiomyopathy, contributing to systolic and diastolic dysfunction. We have recently developed a mouse model of fibrotic noninfarctive cardiomyopathy due to brief repetitive myocardial ischemia and reperfusion. In this model, fibrotic changes are preceded by marked and selective induction of the CC chemokine monocyte chemoattractant protein-1 (MCP-1). We hypothesized that MCP-1 may mediate fibrotic remodeling through recruitment of mononuclear cells and direct effects on fibroblasts.
  
  
  RESULTS
  Wild-type (WT) and MCP-1-null mice underwent daily 15-minute coronary occlusions followed by reperfusion. Additional WT animals received intraperitoneal injections of a neutralizing anti-MCP-1 antibody after the end of each ischemic episode. Hearts were examined echocardiographically and processed for histological and RNA studies. WT mice undergoing repetitive brief myocardial ischemia and reperfusion protocols exhibited macrophage infiltration after 3 to 5 days and marked interstitial fibrosis in the ischemic area after 7 days, accompanied by ventricular dysfunction. MCP-1-null mice had markedly diminished interstitial fibrosis, lower macrophage infiltration, and attenuated ventricular dysfunction compared with WT animals. MCP-1 neutralization also inhibited interstitial fibrosis, decreasing left ventricular dysfunction and regional hypocontractility. Cardiac myofibroblasts isolated from WT but not from MCP-1-null animals undergoing repetitive myocardial ischemia and reperfusion demonstrated enhanced proliferative capacity. However, MCP-1 stimulation did not induce cardiac myofibroblast proliferation and did not alter expression of fibrosis-associated genes.
  
  
  CONCLUSIONS
  Defective MCP-1 signaling inhibits the development of ischemic fibrotic cardiomyopathy in mice. The profibrotic actions of MCP-1 are associated with decreased macrophage recruitment and may not involve direct effects on cardiac fibroblasts.
authors.affiliation: Section of Cardiovascular Sciences, and DeBakey Heart Center, the Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA. ngf@bcm.tmc.edu
authors.forename: Nikolaos G
authors.initials: NG
authors.lastname: Frangogiannis
authors.forename: Oliver
authors.initials: O
authors.lastname: Dewald
authors.forename: Ying
authors.initials: Y
authors.lastname: Xia
authors.forename: Guofeng
authors.initials: G
authors.lastname: Ren
authors.forename: Sandra
authors.initials: S
authors.lastname: Haudek
authors.forename: Thorsten
authors.initials: T
authors.lastname: Leucker
authors.forename: Daniela
authors.initials: D
authors.lastname: Kraemer
authors.forename: George
authors.initials: G
authors.lastname: Taffet
authors.forename: Barrett J
authors.initials: BJ
authors.lastname: Rollins
authors.forename: Mark L
authors.initials: ML
authors.lastname: Entman
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005260:Female; D005355:Fibrosis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017202:Myocardial Ischemia / Q000209:etiology* / Q000235:genetics / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000209:etiology* / Q000235:genetics / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000473:pathology / Q000502:physiology; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000502:physiology*
chemical_list: C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054390:Receptors, CCR2; D019707:Receptors, Chemokine