BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1) and its major receptor, CC chemokine receptor 2 (CCR2), have been shown to contribute to left ventricular remodeling after myocardial infarction. However, it is unknown whether CCR2 deficiency protects the myocardium after myocardial ischemia-reperfusion. The purpose of the present study was to investigate the effects of CCR2 deficiency on myocardial ischemia-reperfusion injury in mice. METHODS AND RESULTS: Experiments were performed in CCR2(-/-) and wild-type mice subjected to 45 min of ischemia followed by reperfusion. Macrophage infiltration in ischemic lesions was markedly reduced in CCR2(-/-) mice compared with wild-type mice (p<0.01). The infarct size was significantly reduced in CCR2(-/-) mice compared with wild-type mice at 3 days after reperfusion (p<0.001). In situ zymography revealed augmented gelatinolytic activity at 3 days after reperfusion in wild-type mice, but significantly less activity in CCR2(-/-) mice. NADPH oxidase activity, the intensity of nitrotyrosine staining and expression of inducible nitric oxide synthase and thioredoxin-1 were significantly increased in ischemic myocardium in wild-type mice compared with CCR2(-/-) mice, indicating a role for CCR2 in oxidative stress after ischemia-reperfusion. CONCLUSIONS: Inhibition of the MCP-1/CCR2 pathway may be a useful strategy for attenuating myocardial ischemia-reperfusion injury.
BACKGROUND:Monocyte chemoattractant protein-1 (MCP-1) and its major receptor, CC chemokine receptor 2 (CCR2), have been shown to contribute to left ventricular remodeling after myocardial infarction. However, it is unknown whether CCR2 deficiency protects the myocardium after myocardial ischemia-reperfusion. The purpose of the present study was to investigate the effects of CCR2 deficiency on myocardial ischemia-reperfusion injury in mice. METHODS AND RESULTS: Experiments were performed in CCR2(-/-) and wild-type mice subjected to 45 min of ischemia followed by reperfusion. Macrophage infiltration in ischemic lesions was markedly reduced in CCR2(-/-) mice compared with wild-type mice (p<0.01). The infarct size was significantly reduced in CCR2(-/-) mice compared with wild-type mice at 3 days after reperfusion (p<0.001). In situ zymography revealed augmented gelatinolytic activity at 3 days after reperfusion in wild-type mice, but significantly less activity in CCR2(-/-) mice. NADPH oxidase activity, the intensity of nitrotyrosine staining and expression of inducible nitric oxide synthase and thioredoxin-1 were significantly increased in ischemic myocardium in wild-type mice compared with CCR2(-/-) mice, indicating a role for CCR2 in oxidative stress after ischemia-reperfusion. CONCLUSIONS: Inhibition of the MCP-1/CCR2 pathway may be a useful strategy for attenuating myocardial ischemia-reperfusion injury.
Authors: John P Cullen; David Morrow; Ying Jin; Nicholas von Offenberg Sweeney; James V Sitzmann; Paul A Cahill; Eileen M Redmond Journal: Atherosclerosis Date: 2007-05-17 Impact factor: 5.162
Authors: Eileen M Redmond; David Morrow; Sreenath Kundimi; Carol L Miller-Graziano; John P Cullen Journal: Atherosclerosis Date: 2008-10-18 Impact factor: 5.162