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

CC趋化因子受体2缺乏可减轻小鼠心肌缺血再灌注引起的氧化应激和梗死面积

• 批准号: 17590752
• 负责人: KAIKITA Koichi
• 金额: $ 2.24万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590752/
• 关键词: myocardial ischemia-reperfusion; CCR2; macrophages; cytokine; oxidative stress; extracellular matrix protein; Matrix metalloproteinase; ケイトカイン

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

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，并作为单核细胞募集的趋化和活化因子。CC趋化因子受体2（CCR 2）是MCP-1的主要受体，MCP-1似乎仅与CCR 2结合。本研究的目的是通过CCR 2基因缺陷小鼠研究单核细胞炎症反应与心肌缺血再灌注损伤的关系。实验在经历45分钟左冠状动脉闭塞然后再灌注的CCR 2 ^<-/->和野生型小鼠中进行。再灌注后6 h、1、3、7 d处死动物。在野生型小鼠中，巨噬细胞浸润逐渐增加，并在再灌注后3天达到峰值。然而，在CCR 2 ^<-/->小鼠中，该过程显著减少（P<0.01）。与野生型小鼠相比，CCR 2 ^<-/->小鼠在重复给药后3天， ...更多信息 灌流组与对照组比较差异有显著性（P<0.001）。为了确定巨噬细胞浸润对心肌纤维化的影响，我们在再灌注后7天测定羟脯氨酸以定量胶原含量。羟脯氨酸含量测定显示，两组缺血心肌再灌注后7天胶原含量均明显高于非缺血或假手术心肌。野生型小鼠缺血心肌中的胶原含量也显著高于CCR 2 ^<-/->小鼠（分别为0.92±0.1 μg/mg vs. 0.54±0.1 μg/mg; P<0.01）。原位酶谱显示野生型小鼠再灌注后3天明胶分解活性增强，但CCR 2 ^<-/->小鼠的活性显著降低。与野生型小鼠相比，CCR^<-/->小鼠缺血心肌中NADPH氧化酶活性、硝基酪氨酸染色强度以及诱导型一氧化氮合酶和硫氧还蛋白-1的表达显著降低。这些结果表明，阻断CCR 2信号传导可减轻缺血再灌注后的氧化应激和心肌损伤。少

项目成果

Reduced von Willebrand factor-cleaving protease (ADAMTS13) activity in acute myocardial infarction

• DOI: 10.1111/j.1538-7836.2006.02161.x
• 发表时间: 2006-11-01
• 期刊: JOURNAL OF THROMBOSIS AND HAEMOSTASIS
• 影响因子: 10.4
• 作者: Kaikita, K.;Soejima, K.;Ogawa, H.
• 通讯作者: Ogawa, H.

Targeted deletion of class A macrophage scavenger receptor increases the risk of cardiac rupture after experimental myocardial infarction

• DOI: 10.1161/circulationaha.106.671198
• 发表时间: 2007-04-10
• 期刊: CIRCULATION
• 影响因子: 37.8
• 作者: Tsujita, Kenichi;Kaikita, Koichi;Takeya, Motohiro
• 通讯作者: Takeya, Motohiro

MCP-1/CCR2 signalling pathway regulates hyperoxia-induced acute lung injury via nitric oxide production I.

MCP-1/CCR2 信号通路通过一氧化氮的产生调节高氧诱导的急性肺损伤 I。

• 发表时间: 2006
• 期刊: Int J Exp Path. 87
• 作者: Makino N;Maeda T;Sugano M;Satoh S;Watanabe R;Abe N;Tsujita K.;Hayasaki T;Kaikita K;Okuma T.
• 通讯作者: Okuma T.

MCP-1/CCR2 signalling pathway regulates hyperoxia-induced acute lung injury via nitric oxide production

• DOI: 10.1111/j.1365-2613.2006.00502.x
• 发表时间: 2006-12-01
• 期刊: INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY
• 影响因子: 3
• 作者: Okuma, Toshiyuki;Terasaki, Yasuhiro;Takeya, Motohiro
• 通讯作者: Takeya, Motohiro

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

• DOI: 10.1253/circj.70.342
• 发表时间: 2006-03-01
• 期刊: CIRCULATION JOURNAL
• 影响因子: 3.3
• 作者: Hayasaki, T;Kaikita, K;Takeya, M
• 通讯作者: Takeya, M