CC chemokine receptor-2 deficiency attenuates oxidative stress and infarct size caused by myocardial ischemia-reperfusion in mice.
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.


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.
Hayasaki
Takanori
T
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Japan.
Kaikita
Koichi
K
Okuma
Toshiyuki
T
Yamamoto
Eiichiro
E
Kuziel
William A
WA
Ogawa
Hisao
H
Takeya
Motohiro
M
D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D018932:Chemokine CCL2 / Q000235:genetics / Q000502:physiology; D016207:Cytokines / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D007150:Immunohistochemistry; D008264:Macrophages / Q000737:chemistry / Q000473:pathology / Q000502:physiology; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000737:chemistry / Q000473:pathology / Q000502:physiology; D009203:Myocardial Infarction / Q000209:etiology* / Q000473:pathology* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000737:chemistry / Q000473:pathology; D009504:Neutrophils / Q000737:chemistry / Q000473:pathology / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000032:analysis / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction
C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D020782:Matrix Metalloproteinases