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）已显示可维持EC功能以防止动脉粥样硬化。 NO由内皮NO合酶产生。 ADMA（非对称二甲基精氨酸）充当内源性NO抑制剂，其水平升高，高脂血症，高血糖和慢性肾脏疾病。但是，尚不清楚ADMA合成对内皮功能的影响尚不清楚。 ADMA是由蛋白质精氨酸N-甲基转移酶（PRMT）合成的。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水平增加到3.8倍，而没有水平降至42％。将TIE2-PRMT-TG与APOE缺陷型小鼠（APOE-KO）交叉，以生成TIE2-PRMT-TG/APOE-KO小鼠。与Apoe-KO相比，在西方饮食后8周，TIE2-PRMT-TG/APOE-KO显示了动脉粥样硬化。 PRMT-TG/APOE-KO中eNOS的1177ser磷酸化水平降低了。此外，链链球菌诱导的高血糖诱导的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抑制了NO，以促进内皮功能障碍。

项目成果

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.