microRNA-451a在血管紧张素Ⅱ诱导的高血压及血管损伤中的作用及分子机制

MicroRNAs are important regulators of vascular remodeling. Our previous study suggested that miR-1185 plays an important role in the regulation of vascular endothelial dysfunction and arterial stiffness. Our previous miRNA microarray data showed that miR-451a expression was significantly decreased compared with control in AngⅡ-induced mouse model of hypertension. Treatment of mice with miR-451a agomir significantly inhibited the increase of blood pressure and blood vessel thickness, and the occurrence of vascular fibrosis induced by AngⅡ. However, the molecular mechanisms for down-regulating miR-451a expression and regulating hypertension need to be explored. However, the pathophysiological mechanism and the target genes of miR-451a still need further study. Here we use AngⅡor DOCA / salt model of hypertension, the application of miR-451a agomir / antagomir or miR-451a mimic / inhibitor-treated mice and cultured cell model in vitro to investigate the mechanisms of down-regulation of miR-451a and the role of miR-451a in vascular remodeling and hypertension and underlying mechanisms. To clarify the direct role of miR-451a target genes and their molecular mechanisms. Finally, elucidate the pathophysiological mechanism of miR-451a in the regulation of hypertension and provide novel targets for prevention and treatment of hypertension.

microRNAs是调控血管重构重要因子。我们既往研究发现miR-1185在调节血管内皮细胞损伤及硬度中发挥重要作用。我们前期在AngⅡ诱导的小鼠高血压模型中，通过microarray筛选发现miR-451a表达明显降低。在小鼠过表达miR-451a可明显降低AngⅡ引起的血压升高、血管增厚及胶原沉积。但是miR-451a作用的机制、调控的靶基因仍需深入研究。本课题将采用AngⅡ灌注或DOCA/salt建立高血压模型，应用miR-451a agomir/antagomir或mimic/inhibitor处理小鼠、内皮/平滑肌/巨噬细胞，探讨AngⅡ灌注或DOCA/salt调节miR-451a表达的分子机制；明确miR-451a在高血压及血管重构中的作用及病理生理机制；阐明miR-451a调控靶基因的分子机制。最终为明确miR-451a在高血压及血管损伤中的作用机制及寻找新靶点提供新依据。

项目背景：microRNA（miRNAs）是调控血管重构的重要因子。既往研究发现miRNA-451a在调控缺血性心脏损伤中发挥重要作用。但是miRNA-451a在血管紧张素II（Ang II）诱导的高血压和血管损伤中的作用和机制仍然未知。.主要研究内容：（1）研究miR-451a在高血压及血管重构中的作用及病理生理机制；（2）明确miR-451a调控的靶基因；（3）探讨miR-451a对巨噬细胞M1/M2表型分化的影响及其相关的分子机制。.重要结果及科学意义：（1）阐明了miR-451a在Ang II诱导的高血压及血管损伤中的作用及病理生理机制；（2）明确了miR-451a的靶基因是β5i；（3）明确了miR-451a在巨噬细胞中特异性的调控β5i的表达；（4）阐明了 miR-451a对巨噬细胞表型分化的影响及其相关的分子机制。（5）明确了miR-451a表达降低可通过与靶基因β5i直接作用，进而激活NF-κB和STAT1信号通路，从而调控巨噬细胞表型分化，导致高血压及血管损伤发生的分子机制。本课题为心血管疾病的防治提供新思路。