A carvedilol-responsive microRNA, miR-125b-5p protects the heart from acute myocardial infarction by repressing pro-apoptotic bak1 and klf13 in cardiomyocytes

• Published in: Journal of molecular and cellular cardiology Vol. 114; pp. 72 - 82
• Main Authors: Bayoumi, Ahmed S., Park, Kyoung-mi, Wang, Yongchao, Teoh, Jian-peng, Aonuma, Tatsuya, Tang, Yaoliang, Su, Huabo, Weintraub, Neal L., Kim, Il-man
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.01.2018
• Subjects: Apoptotic genes; Biased G protein-coupled receptor signaling; Cardioprotection; MicroRNAs; β-arrestin; GRK; KO; CM; LV; sI/R; I/R; DCM; P; MiRNAs or MiRs; Cardioprotection; NRVCs; β-arrestin; Biased G protein-coupled receptor signaling; MicroRNAs; GPCR; β-blockers; MI; Apoptotic genes; Carv; WT; HF; βARs
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2017.11.003

Cardiac injury is accompanied by dynamic changes in the expression of microRNAs (miRs), small non-coding RNAs that post-transcriptionally regulate target genes. MiR-125b-5p is downregulated in patients with end-stage dilated and ischemic cardiomyopathy, and has been proposed as a biomarker of heart failure. We previously reported that the β-blocker carvedilol promotes cardioprotection via β-arrestin-biased agonism of β1-adrenergic receptor while stimulating miR-125b-5p processing in the mouse heart. We hypothesize that β1-adrenergic receptor/β-arrestin1-responsive miR-125b-5p confers the improvement of cardiac function and structure after acute myocardial infarction. Using cultured cardiomyocyte (CM) and in vivo approaches, we show that miR-125b-5p is an ischemic stress-responsive protector against CM apoptosis. CMs lacking miR-125b-5p exhibit increased susceptibility to stress-induced apoptosis, while CMs overexpressing miR-125b-5p have increased phospho-AKT pro-survival signaling. Moreover, we demonstrate that loss-of-function of miR-125b-5p in the mouse heart causes abnormalities in cardiac structure and function after acute myocardial infarction. Mechanistically, the improvement of cardiac function and structure elicited by miR-125b-5p is in part attributed to repression of the pro-apoptotic genes Bak1 and Klf13 in CMs. In conclusion, these findings reveal a pivotal role for miR-125b-5p in regulating CM survival during acute myocardial infarction. [Display omitted] •MiR-125b-5p protects the heart against myocardial infarction.•MiR-125b-5p functions as a gatekeeper of cardiomyocyte survival.•The action of miR-125b-5p is mediated by the repression of bak1 and klf13.