Analysis of endothelium-targeted PRMT-overexpressed mice

内皮靶向 PRMT 过表达小鼠的分析

• 批准号: 20790539
• 负责人: TAKEDA Mitsuo
• 金额: $ 2.75万
• 依托单位: Kyoto Prefectural University of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2009
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20790539/
• 关键词: 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

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.

内皮型一氧化氮（NO）已被证明可以维持EC功能以防止动脉粥样硬化。NO由内皮NO合成酶产生。ADMA（不对称二甲基精氨酸）作为内源性NO抑制剂，其水平在高脂血症、高血糖症和慢性肾脏疾病中增加。然而，ADMA合成增加对内皮功能的影响尚不清楚。ADMA由蛋白质精氨酸N-甲基转移酶（PRMT）合成。本研究利用Tie-2启动子构建了内皮特异性过表达PRMT的转基因小鼠（Tie 2-PRMT-Tg），以研究ADMA对内皮细胞的影响。我们发现，血清中的ADMA水平增加到3.8倍，而NO水平下降到42%，与对照组相比。将Tie 2-PRMT-Tg与ApoE缺陷型小鼠（ApoE-KO）杂交以产生Tie 2-PRMT-Tg/ApoE-KO小鼠。在西方饮食后8周，与ApoE-KO相比，Tie 2-PRMT-Tg/ApoE-KO显示出减弱的动脉粥样硬化。PRMT-Tg/ApoE-KO中eNOS的1177 Ser磷酸化水平降低。此外，PRMT-Tg/ApoE-KO中链脲佐菌素诱导的高血糖诱导的MCP和TNFa-mRNA合成比ApoE-KO高约3倍。因此，PRMT诱导的ADMA抑制NO促进内皮功能障碍。

项目成果

Overexpression of Tie2-Promoted Activated Fibroblast Growth Factor Receptor 2 in Endothelial Cells Enhances Mature Neovascularization via Akt Signaling Pathway in Mice Hindlimb Ischemia

Tie2 促进的激活成纤维细胞生长因子受体 2 在内皮细胞中的过表达通过 Akt 信号通路增强小鼠后肢缺血的成熟新血管形成

• 发表时间: 2006
• 作者: Takeda M;Tatsumi T;Okigaki M;Matsunaga S;Nishikawa S;Kobara M;Matsubara H
• 通讯作者: Matsubara H

Endothelium-targeted overexpression of constitutively active FGF receptor induces cardioproteciton in mice myocardial infarction.

内皮细胞靶向过度表达组成型活性 FGF 受体可诱导小鼠心肌梗塞的心脏保护作用。

• 发表时间: 2009
• 期刊: J Mol Cell Cardiol 46(5)
• 作者: 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.
• 通讯作者: Matsubara H.

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

Tie2 促进的活化成纤维细胞生长因子受体 2 在内皮细胞中过表达可增强小鼠心肌梗死中的血管生成并通过 Src-Akt-Hif1α 信号通路诱导心脏保护作用

• 发表时间: 2007
• 作者: Matsunaga S;Tatsumi T;Okigaki M;Kishita E;Kimata M;Honsyo S;Takeda M;Nishikawa S;Matoba S;Kobara M;Matsubara H.
• 通讯作者: Matsubara H.