Analysis of endothelium-targeted PRMT-overexpressed mice

内皮性一氧化氮（NO）已被证明维持EC功能以预防动脉粥样硬化。NO由内皮NO合成酶产生。ADMA（不对称二甲基精氨酸）作为一种内源性NO抑制剂，其水平在高脂血症、高血糖症和慢性肾脏疾病中升高。然而，ADMA合成增加对内皮功能的影响尚不清楚。ADMA是由蛋白精氨酸n -甲基转铁酶（PRMT）合成的。我们利用Tie-2启动子（tie -PRMT- tg）以内皮特异性方式产生PRMT过表达的转基因小鼠，研究ADMA在内皮中升高的影响。我们发现，与对照组相比，血清中ADMA水平上升至3.8倍，而NO水平下降至42%。将Tie2-PRMT-Tg与apoe缺陷小鼠（ApoE-KO）杂交，生成Tie2-PRMT-Tg/ApoE-KO小鼠。在西方饮食后8周，与ApoE-KO相比，tie - prmt - tg /ApoE-KO显示动脉粥样硬化减弱。PRMT-Tg/ApoE-KO中eNOS的ser磷酸化水平降低。此外，链脲嘧啶诱导的高血糖诱导PRMT-Tg/ApoE-KO中MCP和TNFa-mRNA in的合成比ApoE-KO高约3倍。因此，prmt诱导的ADMA抑制NO促进内皮功能障碍。

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.