microRNA-29b介导血管平滑肌细胞AT1aR基因DNA去甲基化参与高血压发病机制的研究

项目名称： microRNA-29b介导血管平滑肌细胞AT1aR基因DNA去甲基化参与高血压发病机制的研究

项目编号： No.81200193

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学一处

项目作者： 裴芳

作者单位： 中国人民解放军第三军医大学

项目金额： 23万元

中文摘要： 血管紧张素II 1型受体（AT1R）过度表达在高血压发生发展过程中具有重要作用，但AT1R表达上调的机制尚不明确。我们的前期工作发现高血压状态下动脉平滑肌细胞中AT1R的重要亚型-AT1aR启动子区去甲基化并伴有miR-29b高表达。有证据显示DNA甲基转移酶3A/B（DNMT3A/B）和组蛋白去乙酰化酶4（HDAC4）是miR-29b的靶基因。在肿瘤的研究中发现miR-29b可以通过直接靶向抑制DNMT3A/B使DNA去甲基化，HDACs也可通过影响DNMTs影响DNA去甲基化。我们的预实验发现siRNA抑制HDAC4后AT1aR的甲基化水平下调、mRNA水平升高。因此，我们推测miR-29b通过直接抑制DNMTs和靶向抑制HDAC4间接影响DNMTs介导DNA去甲基化，上调AT1aR的表达和功能。此研究有助于揭示高血压状态下AT1aR表达和功能异常的原因，为高血压的防治提供理论基础。

中文关键词： 高血压；血管紧张素1a受体；miR-29b；DNA甲基化；血管平滑肌细胞

英文摘要： Angiotensin II type 1 receptor (AT1R) overexpression is important in the genesis and progression of hypertension. But the mechanism of the upregulation of AT1R is not clear. Our preliminary study discovered that the promoter region of angiotensin II receptor subtype 1a (AT1aR) in vascular smooth muscle cells was getting demethylated during development of hypertension. In addition, miR-29b was upregulated in spontaneously hypertensive rat (SHR). DNA methyltransferase (DNMT)3A, DNMT3B and histone deacetylases (HDAC)4 have been verified as direct target genes of miR-29b. Some previous studies of tumor have suggested that the miR-29b can induce DNA demethylation by directly targeting DNMT3A and DNMT3B. Furthermore, HDACs can induce DNA demethylation by effecting DNMTs. In preliminary experiment，we found that transfection of HDAC4 could induce DNA demethylation and decrease mRNA level of AT1aR. Therefore, we supposed that miR-29b can induce DNA demethylation by targeting directly DNMT3A and DNMT3B and indirectly DNMTs via HDAC4, which promotes the expression and function of AT1aR in hypertension. This study will contribute to elucidating the mechanisms of the abnormal expression and function of AT1R in hypertension, which is beneficial to providing theoretical basis for prevention and treatment of hypertension.

英文关键词： Hypertension；Angiotensin II receptor subtype 1a；MicroRNA-29b；DNA demethylation；Vascular smooth muscle cells