Enhanced MiR-711 transcription by PPARγ induces endoplasmic reticulum stress-mediated apoptosis targeting calnexin in rat cardiomyocytes after myocardial infarction

MicroRNA 711 (miR-711) levels in the heart change dynamically after myocardial infarction (MI). As peroxisome proliferator-activated receptor gamma (PPAR gamma) can upregulate miR-711 in adipocytes and cardiac fibroblasts, this study examined the precise mechanism of PPAR gamma-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 PPAR gamma expression in cardiomyocyte nuclei after MI. PPAR gamma 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 up regulating 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 PPARy 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.