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.

内皮一氧化氮 (NO) 已被证明可以维持 EC 功能以预防动脉粥样硬化。 NO由内皮NO合酶产生。 ADMA（不对称二甲基精氨酸）作为一种内源性 NO 抑制剂，其水平在高脂血症、高血糖和慢性肾病时会升高。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。我们使用 Tie-2 启动子 (Tie2-PRMT-Tg) 生成了 PRMT 以内皮特异性方式过表达的转基因小鼠，以研究内皮细胞中 ADMA 增加的影响。我们发现，与对照相比，血清中的 ADMA 水平增加至 3.8 倍，而 NO 水平下降至 42%。 Tie2-PRMT-Tg 与 ApoE 缺陷小鼠 (ApoE-KO) 杂交产生 Tie2-PRMT-Tg/ApoE-KO 小鼠。西方饮食后 8 周，与 ApoE-KO 相比，Tie2-PRMT-Tg/ApoE-KO 显示动脉粥样硬化减弱。 PRMT-Tg/ApoE-KO 中 eNOS 的 1177Ser 磷酸化水平降低。此外，链托菌素诱导的高血糖诱导 PRMT-Tg/ApoE-KO 中 MCP 和 TNFa-mRNA 的合成比 ApoE-KO 高约 3 倍。因此，PRMT 诱导的 ADMA 抑制 NO 从而促进内皮功能障碍。

项目成果

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

Tie-2 促进的激活成纤维细胞生长因子受体 2 在内皮细胞中的过度表达通过 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: 2007
• 作者: Takeda Mitsuo; Tetsuya Tatsumi; Mitsuhiko Okigaki; Shinsaku Matsunaga; Susumu Nishikawa; Miyuki Kobara; Hiroaki Matsubara
• 通讯作者: Hiroaki Matsubara

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
• 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.