| Project/Area Number |
17591447
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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 |
Digestive surgery
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| Research Institution | Kansai Medical University |
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Principal Investigator |
MATSUI Yoichi Kansai Medical University, Faculty of medicinepitavastatin, Instructor, 医学部, 助手 (60278637)
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| Co-Investigator(Kenkyū-buntansha) |
KAIBORI Masaki Kansai Medical University, Faculty of medicine, Instructor, 医学部, 助手 (30333199)
OKUMURA Tadayoshi Kansai Medical University, Faculty of medicine, Associate Professor, 医学部, 助教授 (80113140)
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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: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | pitavastatin / HMG-CoA reductase inhibitor / nitric oxide / inducible nitric oxide synthase / cirrhosis / primary cultured rat hepatocyte / mRNA stabilizatio / statins / HMG-CoA reductase inhibitor / nitric oxide / inducible nitric oxide synthase / mRNA stabilization / iNOS antisense-transcript / primary cultured hepatocyte / 外科 / シグナル伝達 / 肝障害 |
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| Research Abstract |
Studies have indicated that protective effects of statins (HMG-CoA reductase inhibitor) are associated with the regulation of endothelial nitric oxide synthase (eNOS) or inducible NOS (iNOS) in heart and liver diseases. Statins have been reported to enhance hepatic NO production and decrease the vascular tone in patients with cirrhosis. However, it is unclear which NOS contributes to the increased NO production. We hypothesized that statins are involved in the up-regulation of iNOS in inflammatory liver, resulting in decreased hepatic resistance. Primary cultured rat hepatocytes were treated with pro-inflammatory cytokine interleukin (IL)-1β in the presence or absence of pitavastatin. Pretreatment of cells with pitavastatin resulted in up-regulation of iNOS induction by IL-1β, followed by increased NO production. Pitavastatin had no effects on the degradation of Iκ B or activation of NF-κB. However, pitavastatin super-induced the up-regulation of type I IL-1 receptor (IL-1 RI), which is essential for iNOS induction in addition to the Iκ B/NF-κB pathway. Mevalonate and geranylgeranylpyrophosphate blocked the stimulatory effects of pitavastatin on iNOS and IL-1 RI induction. Transfection experiments revealed that pitavastatin increased the stability of iNOS mRNA rather than its promoter transactivation. In support of this observation, pitavastatin increased the antisense-transcript corresponding to the 3'UTR of iNOS mRNA, which stabilizes iNOS mRNA by interacting with the 3'UTR and RNA-binding proteins. These findings demonstrate that pitavastatin up-regulates iNOS by the stabilization of its mRNA, presumably through the super-induction of IL-1 RI and antisense-transcript. Statins may contribute to a novel potentiated treatment in liver injuries including cirrhosis.
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