PPARγ调控miR-711/148b发挥抑制心肌梗死后内质网应激诱导心肌细胞凋亡的作用及机制研究

Cardiac remodeling after myocardial infarction is an important pathological change leading to the development of heart failure, but there is no ideal means of prevention and treatment for it. Previous work suggests that the expression of miR-711/148b decreased with the course of cardiac remodeling after myocardial infarction. Bioinformatics analysis identified the common predicted targets of miR-711/148b, are related with the endoplasmic reticulum stress-induced apoptosis. In addition, PPARγ, which was reported to be related to cardiomyocyte apoptosis, can up-regulate the expression of miR-711/148b. Whether PPARγ inhibits the endoplasmic reticulum stress-induced apoptosis via miR-711/148b and what is the underlying molecular mechanisms, remain to be elucidated. Therefore, the subject was to investigate and verify to regulate miR-711/148b by interventing with PPARγ, could inhibit the cardiac remodeling after myocardial infarction. This research project providing new clues for prevention of myocardial apoptosis after myocardial infarction.

心肌梗死后心脏重塑是心力衰竭发生发展的重要病理改变，但是目前尚无理想的防治手段。前期研究工作发现miR-711/148b在心肌梗死后心脏重塑中表达下调；生物信息学预测的miR-711/148b共同靶基因与内质网应激诱导的细胞凋亡相关。此外，参与抑制心肌细胞凋亡的PPARγ能上调miR-711/148b表达。那么PPARγ能否通过调控miRNA-711/148b抑制心肌梗死后内质网应激诱导的心肌细胞凋亡及其分子机制是什么尚不清楚。因此，本课题拟探讨干预PPARγ调控miRNA-711/148b的机制，进一步验证其能否抑制心肌梗死后心脏重塑及其机制，本研究有望为心肌梗死后心肌细胞凋亡的防治提供新的线索。

心力衰竭（心衰）是各类心脏疾病终末期共同病理生理表现，心肌梗死后心衰在各种病因导致的心衰中占有主要地位心脏重塑是心肌梗死后心衰的重要病理过程。心肌细胞凋亡所致的心肌细胞丧失是心脏重塑过程致心力衰竭的关键环节之一。心肌细胞凋亡的发生机制，寻找新的靶点对于心脏重塑的预防及治疗具有重要意义。内质网是调控细胞凋亡的重要亚细胞器之一，内质网应激诱导的细胞凋亡在心力衰竭发生中具有重要调控作用。内质网应激在细胞凋亡和细胞生存之间扮演双重角色。MiRNAs在二者之间转换过程中扮演精细调节作用。我们课题组前期在心肌梗死后心力衰竭模型中，发现miR-711及miR-148b表达发生上调。同时，PPARγ能上调miR-711及miR-148b的表达。本课题提出了活化PPARγ 能通过上调miR-711/148b 参与心肌梗死后心脏重塑，导致心力衰竭发生。本课题执行期间应用real-time PCR，western blot，染色质免疫共沉淀，荧光原位杂交，免疫组织化学，流式细胞方法等，荧光素酶报告实验等实验方法证明PPARγ-miR-711-calnexin信号通路参与心肌梗死后内质网应激诱导的细胞凋亡；同时亦证明miR-148b通过PTEN参与抑制心肌梗死后心肌纤维化；以及miRNA-711/148b在心脏重塑中的调控机制，为心肌梗死后心脏重塑的干预提供多个干预治疗靶点。故本研究有望未来向临床应用中转化。