miR-29a对高血压左心室肥厚的作用及分子机制研究

Left ventricular hypertrophy (LVH) is the most common target organ damage of hypertension. It is also an important cause of cardiovascular disease mortality. It is important to clear the mechanism of hypertensive LVH. Recent studies found that miR29a is associated with myocardial fibrosis of hypertrophic cardiomyopathy and myocardial infarction. But, the mechanism of miR29a responsible for myocardial fibrosis are uncertain. Our previous studies found that the level of circulating miR29a increased in hypertensive patients with LVH. And, miR29a expression is elevated in hypertrophic cardiomyocytes and hypertension LVH model. However, The effect and mechanism of miR29a on hypertension LVH is not clear. On the basis of this research, hypertrophic cardiomyocytes and cardiac specific overexpression transgenic mouse model were established. We explore the effect of miR-29a on LVH in hypertension by using gene silencing and over expression method. Next, we further clear the potential target genes for miR-29a and its signal pathway on left ventricular hypertrophy in hypertension. Then, we investagate the effect of targeted intervention miR-29a on left ventricular remodeling in hypertension. Exploration of the molecular mechanisms of miR-29a in hypertensive LVH may help to clearfied the epigenetic mechanisms hypertensive LVH, which is important for looking for the new markers and therapeutic treatment targets to prevent hypertensive LVH.

左心室肥厚（LVH）是高血压最常见的靶器官损害，也是心血管疾病死亡的重要原因。明确高血压LVH的发生机制至关重要。新近研究显示，miR29a与肥厚型心肌病和心肌梗死后的心肌纤维化相关，但具体机制尚不明确。本课题组前期研究发现，高血压LVH患者外周血miR29a水平明显升高，在高血压LVH动物模型和肥大心肌细胞模型中miR29a表达升高，但miR29a对高血压LVH的作用及机制不明确。在此基础上，本课题建立肥大心肌细胞和心脏特异过表达转基因小鼠模型，分别在细胞、分子和动物整体水平，采用基因沉默和过表达方法观察miR-29a在高血压LVH中的作用；并进一步探讨miR-29a潜在的靶基因及其信号通路对高血压LVH的分子调控机制；继而明确靶向干预miR-29a对高血压LVH的影响。本研究结果对于揭示高血压LVH的表观遗传学机制、寻找高血压LVH的新的标记物和治疗靶点具有重要意义。

左心室肥厚（LVH）是高血压最常见的靶器官损害，也是心血管疾病死亡的重要原因。本课题组以人群、实验性左心室肥厚动物模型为研究对象，从整体水平、分子学水平探索 miR-29a潜在的靶基因及分子机制，并进一步探讨靶向干预心肌miR-29a 对高血压 LVH 的影响。我们首先以高血压人群为研究对象，研究发现高血压伴LVH患者血浆 miR⁃29a表达水平明显升高，且血浆 miR⁃29a水平与LVH相关，结果表明血浆 miR⁃29a可能是高血压 LVH新的分子标志物；之后以实验性LVH小鼠为研究对象，探讨miR-29a对左心室重塑的调控及其分子机制，研究发现小鼠左室心肌肥厚组织中miR-29a及胶原表达水平显著升高；心肌过表达miR-29a可改善AngⅡ诱导的小鼠左室重构及病理性心脏肥大，减少心肌组织ColⅠ和Col Ⅲ的表达并伴有TGF-β和p-Smad2/3表达下降，而敲低心肌miR-29a可以加重AngⅡ诱导的左室重构及病理性心脏肥大；进一步应用生物信息学预测miR-29a可能的潜在的靶基因，进一步通过双萤光素酶实验检测miR-29a对目的基因 （ColⅠA1和ColⅢA1）的抑制作用，结果证实miR-29a是通过直接和间接的抑制靶基因ColⅠA1、ColⅢA1的表达来起作用的。因而本研究证实了miR-29a参与了左心室重塑的调控，ColⅠA1和ColⅢA1为miR-29a调控左心室重塑的靶基因。miR-29a逆转心肌重塑的机制：一方面通过直接抑制靶基因ColⅠA1和ColⅢA1抑制胶原的表达；另一方面可能通过抑制TGG-β/磷酸化的smad2/3通路，抑制胶原的表达，从而抑制心肌纤维化。因此，miR-29a可能是抑制左室重构潜在的治疗靶点。