生物钟核受体Rev-erbα在梗死后心肌重构中对血管新生和自噬的双重调控作用及机制

Ischemic heart disease was the leading cause of morbidity and mortality worldwide. Although punctual reperfusion therapies have reduced the mortality of acute myocardial infarction, the prevalence of post-infarction heart failure remains prevalent, calling for exploitation of effective therapies. Our previous studies demonstrated that a circadian receptor retinoid-related orphan nuclear receptor α (RORα) was an endogenous cardioprotective receptor against ischemic cardiac injury and myocardial remodeling, suggesting a therapeutic potential of RORα activation in attenuating post-infarction remodeling and heart failure. However, our further study observed potential metabolic side effect of RORα activation, precluding the translation of RORα activation for treating post-infarction remodeling. Therefore, we focused on another circadian receptor nuclear receptor subfamily 1 group d member 1, also known as Rev-erbα. In the preliminary experiment, we found that Rev-erbα levels were decreased during MI-induced cardiac remodeling in mouse heart, and Rev-erbα played positive role in regulating endothelial tube formation. Moreover, it was reported that Rev-erbα plays a key role in mitochondrial biogenesis and autophagy. Thus, we postulate that Rev-erbα may implicate in the pathogenesis of post-infarction remodeling by regulating angiogenesis and autophagy. The present study was designed to investigate the key role of Rev-erbα in the pathogenesis of post-infarction remodeling, by using molecular biological techniques combined with in vivo/in vitro gene manipulation. The results of our study would provide novel insight into the pathogenesis of post-infarction remodeling, and may provide novel therapeutic target in treating this condition.

我们前期研究发现，生物钟核受体RORα在急性心肌梗死及心肌重构中发挥重要作用，提示其为梗死后心肌重构的潜在干预靶点。但是深入研究发现，激活RORα受体可能会引起严重代谢紊乱。因此，我们进一步研究了生物钟核受体家族的另一名成员Rev-erbα，通过预实验发现Rev-erbα在梗死后心肌组织中显著下调，并在内皮细胞成管作用中发挥关键作用。同时有报道指出，Rev-erbα在维持正常自噬功能和线粒体氧化呼吸功能中发挥重要调控作用。据此推测，核受体Rev-erbα的表达改变可能通过影响心梗后血管新生和自噬功能，最终影响梗死后心肌重构的发展。本课题拟利用全身性和心脏特异性基因敲除小鼠构建心肌梗死模型，通过小动物心脏彩超、活体成像等手段进行功能学检查，结合转录组测序、免疫共沉淀、免疫荧光等分子生物学方法，阐明核受体Rev-erbα在梗死后心肌重构中的关键作用及其机制，为筛选潜在干预靶点提供新思路。

背景：急性心肌梗死严重威胁人类生命健康，其死亡率在我国居心血管疾病首位。尽管再灌注治疗能够及时挽回大多数急性心梗患者的生命，但是部分心肌组织仍然发生坏死，逐渐向心力衰竭发展。然而，目前临床尚缺乏有效的心梗后心肌保护作用靶点。.研究内容：本项目利用整体动物模型和离体细胞模型，通过采用小动物心脏彩超、小动物磁共振、活体成像等手段进行功能学检查，结合转录组测序、免疫组化、免疫荧光等分子生物学方法，检测生物钟核受体Rev-erbα/NR1D1及与其类似的生物钟核受体成员RORα/NR1F1及转录因子超家族成员ZHX2在心肌梗死、心肌重构及代谢综合征中的表达改变及作用。.研究结果：我们首先创建了一种新型高效的心肌梗死模型建立方法；在此基础上，我们发现昼夜节律紊乱显著促进心肌梗死后心肌损伤，这与生物钟核受体Rev-erbα/NR1D1在心肌组织中表达发生下调密切相关。生物钟核受体Rev-erbα/NR1D1通过影响炎症反应级联，在心梗后心肌损伤中发挥重要的保护作用；在进一步研究中，我们发现与Rev-erbα/NR1D1类似的生物钟核受体成员RORα/NR1F1在慢性心肌重构及脑缺血损伤中也发挥类似的保护作用，这一作用与抑制氧化应激密切相关；最后，我们还发现与Rev-erbα/NR1D1同为转录因子超家族成员的ZHX2在代谢综合征中发挥重要的保护作用。.结论及意义：生物节律紊乱对梗死后心肌损伤产生显著的不良影响；而生物钟核受体Rev-erbα/NR1D1及RORα/NR1F1则在急性心肌梗死后心肌损伤及慢性心肌重构中发挥重要的保护作用。这些发现为心肌梗死后损伤及慢性重构的治疗提供了新思路。