| Project/Area Number |
20790539
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Kyoto Prefectural University of Medicine |
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Principal Investigator |
TAKEDA Mitsuo Kyoto Prefectural University of Medicine, 医学部, 博士研究員 (50433256)
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| Project Period (FY) |
2008 – 2009
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| Project Status |
Completed (Fiscal Year 2009)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2009: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2008: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
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| Keywords | eNOS,PRMT,ADMA,血管内皮細胞 / トランスジェニックマウス / 一酸化窒素 / 動脈硬化 / ADMA / 血管内皮細胞 |
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| Research Abstract |
Endothelial Nitric Oxide (NO) has been shown to maintain EC function to prevent atherosclerosis. NO is produced by endothelial NO synthase. ADMA (asymmetric dimethylarginine) acts as an endogenous NO inhibitor and its level increases in hyperlipidemia, hyperglycemia, and chronic renal disease. However, the effect of increased ADMA synthesis on endothelial function was not clear. ADMA was synthesized by protein arginine N-methyltrans-ferases (PRMT). We generated the transgenic mice in which PRMT was over-expressed in endothelium-specific manner using Tie-2 promoter (Tie2-PRMT-Tg) to study the effect of increased ADMA in endothelium. We found that ADMA level in the serum increased to 3.8-fold, whereas NO level decreased to 42%, compared to the control. Tie2-PRMT-Tg were crossed with ApoE-deficient mice (ApoE-KO) to generate Tie2-PRMT-Tg/ApoE-KO mice. At 8 weeks after Western diet, the Tie2-PRMT-Tg/ApoE-KO shows attenuated atherosclerosis, compared to ApoE-KO. 1177Ser phosphorylation level of eNOS in the PRMT-Tg/ApoE-KO was decreased. Furthermore, streptoztocine-induced hyperglycemia induced synthesis of MCP and TNFa-mRNA in in PRMT-Tg/ApoE-KO was ~3 fold higher than ApoE-KO. Thus, PRMT-Induced ADMA inhibited NO to promote endothelial dysfunction.
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