Project/Area Number |
17590752
|
Research Category |
Grant-in-Aid for Scientific Research (C)
|
Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Circulatory organs internal medicine
|
Research Institution | Kumamoto University |
Principal Investigator |
KAIKITA Koichi Kumamoto University, Graduate School of Medical Sciences, Department of Cardiovascular Medicine, Assistant Professor, 大学院医学薬学研究部, 講師 (30346978)
|
Project Period (FY) |
2005 – 2006
|
Project Status |
Completed (Fiscal Year 2006)
|
Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2005: ¥2,400,000 (Direct Cost: ¥2,400,000)
|
Keywords | myocardial ischemia-reperfusion / CCR2 / macrophages / cytokine / oxidative stress / extracellular matrix protein / Matrix metalloproteinase / ケイトカイン |
Research Abstract |
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
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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
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