Department of Cardiovascular Medicine, Shaanxi Province People's Hospital, Xi'an, Shaanxi, China.
Department of Medical Affairs, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China.
J Mol Cell Cardiol. 2018 May;118:36-45. doi: 10.1016/j.yjmcc.2018.03.006. Epub 2018 Mar 6.
MicroRNA 711 (miR-711) levels in the heart change dynamically after myocardial infarction (MI). As peroxisome proliferator-activated receptor gamma (PPARγ) can upregulate miR-711 in adipocytes and cardiac fibroblasts, this study examined the precise mechanism of PPARγ-mediated miR-711 upregulation and its role in the heart in the early stages after MI. In a rat model of MI induced by left anterior descending coronary artery ligation, immunohistochemical and western blot analyses revealed increased PPARγ expression in cardiomyocyte nuclei after MI. PPARγ modulated miR-711 levels in neonatal rat cardiomyocytes, and chromatin immunoprecipitation and luciferase assays revealed that it bound the premiR-711 promoter to upregulate miR-711. Bioinformatics analysis identified calnexin as a putative miR-711 target; this was confirmed by luciferase, western blot, and real-time polymerase chain reaction analyses. Additionally, the transfection of a miR-711 mimic into cardiomyocytes induced the endoplasmic reticulum (ER) stress-induced apoptosis response by upregulating glucose-regulated protein 78 (GRP78), activating transcription factor (ATF6), spliced X-box binding protein 1 (XBP1), apoptotic signal-regulating kinase 1 (ASK1), CCAAT-enhancer binding protein homologous protein (CHOP), caspase-12, and endoplasmic reticulum oxidoreductase 1 alpha (ERO1a). Similarly, on day 2 after MI, increased miR-711 levels in the heart were accompanied by increased cardiomyocyte apoptosis, decreased calnexin levels, and increased levels of GRP78, ATF6, spliced XBP1, ASK1, CHOP, and caspase-12, as well as cardiomyocytes apoptosis. The mechanism underlying these effects may involve the direct binding of PPARγ to the pre-miR-711 promoter for the upregulation of miR-711, which may induce ER stress-mediated cardiomyocyte apoptosis via calnexin. These findings augment the general knowledge of the post-MI pathological process and suggest a therapeutic strategy for cardiac remodelling in the early stages after MI.
心肌梗死后（MI）心脏中的 microRNA 711（miR-711）水平会发生动态变化。由于过氧化物酶体增殖物激活受体γ（PPARγ）可以在脂肪细胞和心肌成纤维细胞中上调 miR-711，因此本研究检查了 PPARγ 介导的 miR-711 上调的精确机制及其在 MI 后早期心脏中的作用。在左前降支冠状动脉结扎诱导的大鼠 MI 模型中，免疫组织化学和 Western blot 分析显示 MI 后心肌细胞核中 PPARγ 表达增加。PPARγ 调节新生大鼠心肌细胞中的 miR-711 水平，染色质免疫沉淀和荧光素酶测定显示其结合 premiR-711 启动子以上调 miR-711。生物信息学分析鉴定钙连蛋白为 miR-711 的潜在靶标；通过荧光素酶、Western blot 和实时聚合酶链反应分析证实了这一点。此外，miR-711 模拟物转染心肌细胞通过上调葡萄糖调节蛋白 78（GRP78）、激活转录因子（ATF6）、剪接 X 盒结合蛋白 1（XBP1）、凋亡信号调节激酶 1（ASK1）、CCAAT 增强子结合蛋白同源蛋白（CHOP）、半胱天冬酶-12 和内质网氧化还原酶 1α（ERO1a）诱导内质网（ER）应激诱导的细胞凋亡反应。同样，在 MI 后第 2 天，心脏中 miR-711 水平升高伴随着心肌细胞凋亡增加、钙连蛋白水平降低以及 GRP78、ATF6、剪接 XBP1、ASK1、CHOP 和半胱天冬酶-12 水平升高，以及心肌细胞凋亡。这些作用的机制可能涉及 PPARγ 与 pre-miR-711 启动子的直接结合以上调 miR-711，这可能通过钙连蛋白诱导 ER 应激介导的心肌细胞凋亡。这些发现增加了对 MI 后病理过程的一般认识，并为 MI 后早期心脏重塑提供了一种治疗策略。
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