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

Ahmed S. Bayoumi, Kyoung mi Park, Yongchao Wang, Jian peng Teoh, Tatsuya Aonuma, Yao Liang Tang, Huabo Su, Neal Lee Weintraub, Il-man Kim

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Background 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. Methods and results 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. Conclusions In conclusion, these findings reveal a pivotal role for miR-125b-5p in regulating CM survival during acute myocardial infarction.

Original languageEnglish (US)
Pages (from-to)72-82
Number of pages11
JournalJournal of molecular and cellular cardiology
Volume114
DOIs
StatePublished - Jan 2018

Keywords

  • Apoptotic genes
  • Biased G protein-coupled receptor signaling
  • Cardioprotection
  • MicroRNAs
  • β-arrestin

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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