PMID- 17283277
OWN - NLM
STAT- MEDLINE
DCOM- 20070313
LR  - 20220227
IS  - 1524-4539 (Electronic)
IS  - 0009-7322 (Linking)
VI  - 115
IP  - 5
DP  - 2007 Feb 6
TI  - Critical role of monocyte chemoattractant protein-1/CC chemokine ligand 2 in the 
      pathogenesis of ischemic cardiomyopathy.
PG  - 584-92
AB  - 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. METHODS AND 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.
FAU - Frangogiannis, Nikolaos G
AU  - Frangogiannis NG
AD  - Section of Cardiovascular Sciences, and DeBakey Heart Center, the Methodist 
      Hospital, Baylor College of Medicine, Houston, TX 77030, USA. ngf@bcm.tmc.edu
FAU - Dewald, Oliver
AU  - Dewald O
FAU - Xia, Ying
AU  - Xia Y
FAU - Ren, Guofeng
AU  - Ren G
FAU - Haudek, Sandra
AU  - Haudek S
FAU - Leucker, Thorsten
AU  - Leucker T
FAU - Kraemer, Daniela
AU  - Kraemer D
FAU - Taffet, George
AU  - Taffet G
FAU - Rollins, Barrett J
AU  - Rollins BJ
FAU - Entman, Mark L
AU  - Entman ML
LA  - eng
GR  - P01 HL-42550/HL/NHLBI NIH HHS/United States
GR  - R01 HL-76246/HL/NHLBI NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Circulation
JT  - Circulation
JID - 0147763
RN  - 0 (Ccr2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Receptors, CCR2)
RN  - 0 (Receptors, Chemokine)
SB  - IM
MH  - Animals
MH  - Chemokine CCL2/deficiency/genetics/*physiology
MH  - Female
MH  - Fibrosis
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Myocardial Ischemia/*etiology/genetics/*pathology
MH  - Myocardial Reperfusion Injury/*etiology/genetics/*pathology
MH  - Myocytes, Cardiac/pathology/physiology
MH  - Receptors, CCR2
MH  - Receptors, Chemokine/*physiology
EDAT- 2007/02/07 09:00
MHDA- 2007/03/14 09:00
CRDT- 2007/02/07 09:00
PHST- 2007/02/07 09:00 [pubmed]
PHST- 2007/03/14 09:00 [medline]
PHST- 2007/02/07 09:00 [entrez]
AID - 115/5/584 [pii]
AID - 10.1161/CIRCULATIONAHA.106.646091 [doi]
PST - ppublish
SO  - Circulation. 2007 Feb 6;115(5):584-92. doi: 10.1161/CIRCULATIONAHA.106.646091.