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

单核细胞趋化蛋白-1(MCP-1)属于CC趋化因子亚家族，具有两个相邻的半胱氨酸残基，是单核细胞募集的趋化和激活因子。CC趋化因子受体2(CCR2)是MCP-1的主要受体，MCP-1似乎只与CCR2结合。本研究以CCR2基因缺陷小鼠为模型，探讨单核细胞炎症反应与心肌缺血再灌注损伤的关系。实验是在CCR2^&lt；-/-&gt；和野生型小鼠身上进行的，小鼠左冠状动脉闭塞45分钟后再灌注。分别于再灌注后6h、1、3、7d处死动物。野生型小鼠巨噬细胞浸润逐渐增多，再灌流后3d达高峰。然而，这一过程在CCR2^&lt；-/-&gt；小鼠中显著减少(P&lt；0.01)。在REPE…后3天，CCR2^-/-&gt；小鼠的脑梗塞面积与野生型小鼠相比显著缩小更多的回流(P&lt；0.001)。为探讨巨噬细胞浸润在心肌纤维化中的作用，我们在再灌流后7d用羟脯氨酸测定胶原含量。羟脯氨酸测定显示，再灌注7d，两组缺血心肌的胶原含量均明显高于非缺血心肌和假手术心肌。野生型小鼠缺血心肌的胶原含量也显著高于CCR2；-/-GT；小鼠(分别为0.92±0.1μg/mg和0.54±0.1μg/mg；P&lt；0.01)。原位酶谱显示，野生型小鼠在再灌流后3天明胶溶解活性增强，而CCR2；-/-&gt；小鼠的活性显著降低。与野生型小鼠相比，CCR^-lt；-/-&gt；小鼠缺血心肌的NADPH氧化酶活性、硝基酪氨酸染色强度、诱导型一氧化氮合酶和硫氧还蛋白-1的表达均显著降低。这些结果表明，阻断CCR2信号通路可减轻缺血再灌注后的氧化应激和心肌损伤。较少

Monocyte chemoattractant protein-1 (MCP-1) belongs to the CC chemokine subfamily with two adjacent cysteine residues and serves as a chemotactic and activating factor for the recruitment of monocytes. CC chemokine receptor 2 (CCR2) is a major receptor for MCP-1 and MCP-1 appears bind solely to CCR2. The purpose of the present study was to investigate the relationship between the monocytic inflammatory response and myocardial ischemia-reperfusion injury by using mice deficient in the CCR2 gene. Experiments were performed in CCR2^<-/-> and wild-type mice subjected to 45 minutes of left coronary artery occlusion followed by reperfusion. Animals were sacrificed at 6 h and at 1, 3, and 7 days after reperfusion. Macrophage infiltration was gradually increased and peaked at 3 days after reperfusion in wild-type mice. However, this process was markedly reduced in CCR2^<-/-> mice (P<0.01). Infarct size was significantly reduced in CCR2^<-/->mice compared with wild-type mice at 3 days after repe … More rfusion (P<0.001). To determine the effect of macrophage infiltration on myocardial fibrosis, we assayed hydroxyproline to quantitate collagen content at 7 days after reperfusion. The hydroxyproline assay revealed that in both groups the collagen content was increased significantly in ischemic myocardium at 7 days after reperfusion compared with non-ischemic or sham-operated myocardium. Collagen content was also significantly greater in ischemic myocardium of wild-type mice compared with CCR2^<-/-> mice (0.92±0.1 μg/mg vs. 0.54±0.1 μg/mg, respectively; P<0.01). 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 decreased in ischemic myocardium in CCR^<-/-> mice compared with wild-type mice. These results suggest that the blockade of CCR2 signaling attenuates oxidative stress and myocardial injury after ischemia-reperfusion. Less