| Project/Area Number |
15590770
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Keio University |
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Principal Investigator |
SHINMURA Ken Keio University, Department of Medicine, Research and clinical Instructor, 医学部, 助手 (70206332)
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| Co-Investigator(Kenkyū-buntansha) |
NAGAI Maiko Keio University, Department of Medicine, Research and clinical Instructor, 医学部, 助手 (10306714)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2004: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2003: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Keywords | cyclooxygenase / nitric oxide synthase / myocardial infarction / PGE2 synthase / matrix metalloproteinase / fibrosis / ischemia reperfusion injury / ischemic preconditioning / プロスタグランジンE_2 |
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| Research Abstract |
I. Mechanism whereby cardiac and renal fibrosis develops in COX-2^<-/-> knockout mouse
It is well known that cardiac and renal fibrosis develops in cyclooxygenase(COX)-2 knockout mouse with aging, suggesting that COX-2 expressed constitutively in the heart and kidney participants the regulation of fibrosis. To investigate role of COX-2 on the development of cardiac and renal fibrosis, we compared the expression of prostanoid synthases and matrix metalloproteinases(MMPs) between wild-type (WT) and COX-2^<-/-> mice. Eight week-old COX-2^<-/-> mice showed mild renal dysfunction (elevation in blood urea nitrogen) and thinning of renal cortex. The expression of membrane-bound PGE synthase(mPGES) and MMP-2 was decreased in the kidney of COX-2^<-/-> mice, compared with WT mice, and associated with decrease in renal PGE_2 content. Sixteen week-old COX-2^<-/-> mice showed mild interstitial fibrosis in the kidney and decreased expression of mPGES and MMP-2 even in the heart. In conclusion, PGE_2
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derived from functionally-coupled COX-2 and mPGES is essential for resolving fibrosis in the kidney, and probably in the heart.
II. Interaction between COX-2 and inducible nitric oxide synthase(iNOS) in post-infarct myocardium
Recent studies have suggested that COX-2-derived products are involved in the development of post-infarct ventricular remodeling. In addition, it is known that COX-2 protein is induced in concert with iNOS around and at the site of the infarct. Thus, we investigated the role of COX-2 and the interaction between COX-2 and iNOS in post-infarct myocardium using WT and iNOS knockout mice(iNOS^<-/->). In vivo myocardial infarction was produced by ligation of the left anterior descending coronary artery Mice were randomly divided into vehicle- and NS-398-treated groups. Seventy-two h later, infarct size was detected by TTC staining and the expression of COX-2 and iNOS proteins was examined by immunohistolochemical staining. The expression of COX-2 was increased in both strains and similar. iNOS was observed in close proximity to COX-2-positive cells at the periphery of the infarct in WT. There is no difference in infarct size and the mortality between WT and iNOS^<-/-> mice treated with vehicle. Administration of NS-395 tended to reduce infarct size in WT mice but it rather exacerbated infarct size and the mortality in iNOS^<-/-> mice. We speculate that 1)increased COX-2 protein has the deleterious effect in post-infarct myocardium and 2)co-expressed iNOS modulates the deleterious effect of COX-2. Thus, COX-2 might exert the cardioprotective or detrimental action, dependent on iNOS activity. Less
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