| Project/Area Number |
17590219
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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 |
General pharmacology
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| Research Institution | Shiga University of Medical Science |
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Principal Investigator |
SHINOZAKI Kazuya Shiga University of Medical Science, Department of Pharmacology, Associate Professor, 医学部, 助手 (20324577)
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| Co-Investigator(Kenkyū-buntansha) |
OKAMURA Tomio Shiga University of Medical Science, Department of Pharmacology, Professor, 医学部, 教授 (70152337)
AYAJIKI Kazuhide Shiga University of Medical Science, Department of Pharmacology, Assistant Professor, 医学部, 助教授 (10167968)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2005: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Keywords | Insulin resistance / Endothelial dysfunction / Hyperlipidemia / Angiotensin / Oxidative stress / Nitric oxide synthase / Tetrahydrobiopterin / テトラヒドロビオプテリン / 血管内皮機能障害 / 一酸化窒素 / フィブラート / HMG-CoA還元酵素阻害薬 |
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| Research Abstract |
3-Hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors (statins) may benefit the vasculopathy of insulin resistance independent of its lipid lowering effects. Because imbalance of nitric oxide (NO) and superoxide anion (O2^-) formation may lead to vascular dysfunction, we investigated the effect of statin on vasomotion of insulin-resistant state to clarify the mechanism by which statin ameliorates the impaired function. In the isolated aorta, contraction induced by angiotensin II was more potent in Zucker fatty rats (ZF) compared with that in Zucker lean rats. Both angiotensin II type 1 receptor expression and O_2^- production were upregulated in ZF. In addition, deficiency of teterahydrobiopterin (BH4) contributes to the endothelial dysfunction in ZF. Oral administration of pitavastatin for 8 weeks normalized angiotensin II-induced vasoconstriction and endothelial function in ZF. Pitavastatin treatment of ZF increased vascular BH4 content, which was associated with 2-fold increase in endothelial NO synthase (eNOS) activity as well as a 60% reduction in endothelial O_2^- production. The treatment also markedly downregulated protein expression of angiotensin II type 1 receptor and gp9 1phox, whereas expression of GTP cyclohydrolase I was upregulated. Pitavastatin restores vascular dysfunction by inhibiting NAD(P)H oxidase activity and uncoupled eNOS- dependent O_2^- production.
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