外泌体circRNA cZNF292在慢性间歇低氧心肌损伤中的机制研究

Chronic intermittent hypoxia (CIH) induced by obstructive sleep apnea hypopnea syndrome (OSAHS) is an independent risk factor for cardiovascular disease, and circRNA may play an important role in cardiovascular diseases by competitively binding miRNA. Our previous studies have found that miR-146a-5p binded to human nuclear-induced apoptosis factor 1 (NAIF1) inducing cardiomyocyte apoptosis under CIH. Bioinformatics predicts that circRNA cZNF292 forms complementary base pairing with miR-146a-5p, and circRNA is enriched in exosomes. Then the analysis of expression profile of serum exosomal circRNA in patients with myocardial infarction complicated with OSAHS were performed, and we found that serum exosomal circRNA cZNF292 decreased in OSAHS patients with myocardial infarction. Therefore, we hypothesize that the reduced expression of exosomal circRNA cZNF292 might suppress the expression of NAIF1 which could contribute to myocardial injury by increasing the level of miR-146a-5p. The aim of our study are to explore the molecular mechanism of exosomal circRNA cZNF292 in myocardial injury by regulating miR-146a-5p from employing human sample, in vitro cell and animal models, which will provide new ideas for the prevention and treatment of OSAHS-related cardiovascular damage and screening of molecular markers.

阻塞性睡眠呼吸暂停低通气综合征（OSAHS）引起的慢性间歇低氧（CIH）是心血管疾病的独立危险因素，circRNA可通过竞争性结合miRNA参与心血管疾病的发生。前期研究发现CIH下miR-146a-5p结合人核诱导凋亡因子1（NAIF1）诱导心肌细胞凋亡，生物信息学预测circRNA cZNF292与miR-146a-5p形成互补碱基配对，而circRNA在外泌体中含量丰富，临床研究发现心肌梗死的OSAHS患者血清外泌体circRNA cZNF292降低。因此我们猜想CIH下心肌细胞外泌体传递的circRNA cZNF292表达降低，导致miR-146a-5p升高，对NAIF1抑制增强，引起心肌损伤。本研究从临床、体外细胞及动物模型探讨外泌体circRNA cZNF292通过miR-146a-5p调控心肌损伤的分子机制，为OSAHS相关心血管损伤的防治、诊断分子标志物的筛选提供新思路。

阻塞性睡眠呼吸暂停低通气综合征(OSAHS)是高血压、冠心病、心力衰竭等心血管疾病的独立危险因素之一。OSAHS可通过反复的低氧再灌注损伤导致心肌损伤，继而引起相关的心血管事件，但其具体机制仍不清楚。本课题首先发现间歇低氧（IH）下外泌体circRNA cZNF292表达明显降低，同时miR-146a-5p表达升高，继而检测间歇低氧（IH）处理后人心肌细胞（AC16）外泌体中circRNAs及miRNAs的表达情况，发现加入IH上清外泌体的心肌细胞组circRNA cZNF292表达明显降低，同时miR-146a-5p表达升高。根据生物信息学预测及双荧光素酶报告实验，外泌体circZNF292可能通过miR-146a-5p/XIAP轴调控心肌细胞损伤，最后通过回复实验进一步验证了外泌体circRNA cZNF292靶向调控 miR-146a-5p/XIAP改善IH介导的心肌细胞损伤，为OSAHS相关心血管损伤的发生发展、诊断分子标志物的筛选以及临床治疗提供理论基础和实验依据。此外，课题组还进行了铁死亡在IH下心肌损伤中的机制研究，发现铁死亡参与IH相关心肌损伤，抑制铁死亡和乙酰半胱氨酸治疗可缓解IH相关心肌损伤，这可能是OSAHS致心肌损伤治疗方法的潜在靶点。