miR-145 在机械牵张诱导主动脉夹层血管平滑肌细胞表型转化中分子机制

Hypertension is the most common basical disease for the aortic dissection(AD).However,the mechanicsm of the AD induced by hypertension is not clear.It has been confirmed that matrix metallopreoteinase-9(MMP-9) expressed by vascular smooth muscle cell(VSMC) in hypertension patient is very important in AD.Supported by the National Natural Science Foundation(NO.81370414),our study had demonstrated that mechanical strain could induce expression of matrix metalloproteinase-9(MMP-9) in vascular smooth muscle cell(VSMC). The phenotype of VSMC in normal aorta is contractile phenotype,and only synthetic phenotype VSMC can secrete MMP-9. Therefore, it is not clear that the mechanism of regulation of VSMC phenotype differentiation. The studies confirmed mirRNAs involved in regulating VSMCs phenotype differentiation,our previous study had demonstrated that miR-145 was downgulated in AD aortic tissues. We assumed that the mechanisms maybe that miR-145 mediates VSMCs phenotype differentiation induced by mechanical strain in AD aoritc tissues. What’s the regulatory mechanism involved? The object of this study is to ivestigate the regulatory mechanisms of miR-145 in VSMC phenotype differentiation induced by mechanical strain,which will provide a new target of prevention and treatment of AD.

高血压是主动脉夹层（AD）最常见的基础疾病，但高血压导致AD的发生机制不明确。已证实高血压患者主动脉壁中平滑肌细胞（VSMCs）分泌的基质金属蛋白酶-9（MMP-9）在AD的发生过程中起重要作用。血压升高导致血管壁机械牵张力升高，在国家自然基金的资助下，我们首次发现机械牵张能够诱导AD中主动脉VSMCs表达MMP-9。生理状态下VSMCs是收缩型，只有转化为合成型VSMCs才表达MMP-9，是什么机制促使VSMCs表型转化并不清楚。研究证实microRNAs参与调节VSMCs表型转化，我们前期研究发现机械牵张能诱导AD主动脉VSMC表型发生转化，且AD主动脉壁中的miR-145表达下调，故我们推测机械牵张可能通过miR-145调控AD中VSMCs表型转化。但又有怎样的调控机制？本项目旨在探讨miR-145在机械牵张诱导AD中VSMCs表型转化的分子机制，为AD的防治提供新的靶点。

背景:miR-145与血管平滑肌细胞(VSMC)表型转化密切相关;然而，miR-145在机械拉伸作用下调控VSMC表型转化的调控机制尚不清楚。在这项研究中，我们评估了miR-145在主动脉夹层(AD)机械拉伸后的vsmc中的作用。 .方法:采用定量聚合酶链反应法分析miR-145在AD模型动物和患者主动脉壁的表达。利用miR-145相关的蛋白-蛋白相互作用网络和Wikipathways分析miR-145调控的VSMC表型转化通路。我们使用功能获得和功能丧失研究来评估miR-145在机械牵张诱导下对VSMC分化的影响，并评估在机械牵张条件下miR-145是否在主动脉中调控kruppal -like factor 4 (KLF4)。.结果:miR-145在正常人主动脉壁大量表达，但在动物模型和夹层患者主动脉壁中明显下调。我们发现，血管平滑肌细胞受到机械拉伸后，收缩表型相关蛋白表达下调，而分泌表型相关蛋白表达增加。miR-145过表达也可下调血管平滑肌细胞收缩表型相关蛋白，抑制表型相关蛋白的上调。最后，在机械拉伸作用下，VSMCs中KLF4的表达显著增加，而过表达的miR-145阻断了这一作用。.结论:机械拉伸可诱导VSMCs表型转化，通过上调KLF4促进AD的发生;这一机制受到miR-145的调控，miR-145直接调控KLF4的表达和VSMC的分化。