PPARγ-miRNA-711信号通路在心肌梗死后心脏重塑中的作用及机制

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. Our previous work suggests that the expression of miRNA-711 increased in the early remodeling stage after myocardial infarction, and gradually reduced, changing with the course of cardiac remodeling. Bioinformatics analysis identified the predicted targets of miRNA-711, some of the target genes are related with collagen and fibrosis. In addition, the transcription factor PPARγ, which was reported to be related to fibrosis, elevates the expression of miRNA-711. The biological function and significance of miRNA-711 in the process of cardiac remodeling after myocardial infarction, and whether to regulate miRNA-711 by interventing with PPARγ could inhibit the fibrosis after myocardial infarction, and what is the underlying molecular mechanisms, remain to be elucidated. Therefore, the subject was to investigate and verify the role and mechanism of the PPARγ-miRNA-711 signal transduction pathways in cardiac remodeling after myocardial infarction; and the effect of regulating PPARγ-miRNA-711 through different periods in the course of the cardiac remodeling after myocardial infarction. This research project providing new clues for prevention of cardiac fibrosis 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。本课题组的前期工作提示miRNA-711在心肌梗死后心脏重塑的早期表达升高，后逐渐减低，其表达水平随心脏重塑的病程而变化；信息学预测的miRNA-711靶基因中有多个与心肌纤维化发生相关。此外，与纤维化密切相关的转录因子PPARγ可升高miRNA-711的表达。那么，心肌梗死后心脏重塑过程中miRNA-711的生物学功能和意义是什么，干预PPARγ是否可调控miRNA-711的表达进而调控心肌梗死后的纤维化过程以及其分子机制是什么都尚不清楚。因此，本课题拟探讨并验证PPARγ-miRNA-711信号转导通路在心肌梗死心脏重塑中的作用及机制；通过在病程的不同时期干预PPARγ调控miRNA-711的表达，验证其能否抑制心肌梗死后心脏重塑。通过本课题研究，有望为心肌梗死后心脏纤维化的防治提供新的线索。

心肌梗死后心脏重塑是梗死后心脏结构的改变，是心力衰竭发生发展的基础，其防治手段是目前本领域的研究重点。心肌梗死后心脏重塑包括心肌纤维化、心肌细胞缺血性坏死及凋亡、缺血远隔区心肌细胞的过度肥大等病理机制。本课题组前期工作发现，miRNA-711在心肌梗死后心脏重塑的早期表达升高，后逐渐减低，其表达水平随病程进展呈动态变化；同时能够升高miRNA-711的药物吡格列酮被报道具有抑制纤维化的作用。因此，我们开展了本项目研究，旨在探明梗死后心脏重塑病程中表达改变的miRNA-711具有怎样的生物学功能和意义，及miRNA-711的表达调控机制。我们的研究结果验证了课题假说，证实miRNA-711通过作用于靶基因SP1调节下游I型胶原表达水平，发挥抑制心脏纤维化的作用；吡格列酮是一种有效的升高miRNA-711的药物，我们明确了吡格列酮升高miRNA-711的机制是依赖于PPARγ的转录调节，PPARγ可激活miRNA-711的前体和宿主基因的转录水平，并明确验证了PPARγ与pre- miRNA-711启动子区的结合位点。在此基础上，我们进一步关注了梗死后心脏重塑的另外两种主要病理机制，心肌肥大和心肌细胞凋亡，发现过表达miRNA-711可能通过靶向抑制mTOR发挥抑制心肌细胞肥大的作用；高水平miRNA-711通过靶向抑制Calnexin，抑制内质网应激的修复，促进内质网应激介导的心肌细胞凋亡。综上，我们的研究证实，miRNA-711-SP1信号通路及miRNA-mTOR信号通路，在梗死后心脏重塑后期，发挥着抑制心脏纤维化和抑制心肌细胞过度肥大的作用；而在梗死后心脏重塑早期，过高水平的miRNA-711，通过抑制靶基因Calnexin，可能发挥着促内质网应激所介导的心肌细胞凋亡。miRNA-711在心梗后心脏重塑中通过多种调节机制发挥着重要作用，干预心梗后心脏重塑病程中miRNA-711的表达，有望实现对心脏重塑恶性发展的遏制，miRNA-711是一种潜在的防治心梗后心脏重塑进展的靶标。