Analysis of endothelium-targeted PRMT-overexpressed mice

2009 Fiscal Year Final Research Report

• Project/Area Number: 20790539
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Circulatory organs internal medicine
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: TAKEDA Mitsuo Kyoto Prefectural University of Medicine, 医学部, 博士研究員 (50433256)
• Project Period (FY): 2008 – 2009
• Keywords: eNOS,PRMT,ADMA,血管内皮細胞 / トランスジェニックマウス

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.

Research Products

• [Journal Article] Endothelium-targeted overexpression of constitutively active FGF receptor induces cardioproteciton in mice myocardial infarction. (2009)
  • Author(s): Matsunaga S, Okigaki M, Takeda M, Matsui A, Honsyo S, Katsume AA, Kishita E, Jishan C, Kurihara T, Adachi Y, Mansukhani A, Kobara M, Matoba Y, Tatsumi T, Matsubara H.
  • Journal Title: J Mol Cell Cardiol 46(5) Pages: 663-673
• [Presentation] Overexpression of Tie2-promoted Activated Fibroblast Growth Factor Receptor 2 in Endothelial Cells enhances Angiogenesis and Induces Cardioprotective Effect via Src-Akt-Hif1α Signaling Pathway in Mice Myocardial Infarction (2007)
  • Author(s): Matsunaga S, Tatsumi T, Okigaki M, Kishita E, Kimata M, Honsyo S, Takeda M, Nishikawa S, Matoba S, Kobara M, Matsubara H.
  • Organizer: American Heart Association
  • Place of Presentation: Orlando, USA
  • Year and Date: 20071104-20071107
• [Presentation] Overexpression of Tie-2-Promoted Activated Fibroblast Growth Factor Receptor 2 in Endothelial Cells Enhances Mature Neovascularization via Akt Signaling Pathway in Mice Hindlimb Ischemia (2007)
  • Author(s): Takeda Mitsuo, Tetsuya Tatsumi, Mitsuhiko Okigaki, Shinsaku Matsunaga, Susumu Nishikawa, Miyuki Kobara, Hiroaki Matsubara
  • Organizer: American Heart Association
  • Place of Presentation: Orlando, USA
  • Year and Date: 20071104-20071107