Abstract 23928: Microrna-125b-5p Protects The Heart From Acute Myocardial Infarction By Repressing Pro-apoptotic Bak1 And Klf13 In Cardiomyocytes

Abstract

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 showed using the β-arrestin-biased β-blocker, carvedilol that β1-adrenergic receptor-mediated cardioprotective signaling through β-arrestin1 stimulates processing of miR-125b-5p in the mouse heart (Figure A-C). We hypothesize that β1-adrenergic receptor/β-arrestin1-responsive miR-125b-5p confers cardioprotection against 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 an increased sensitivity 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, cardioprotection elicited by miR-125b-5p is in part attributed to repression of the pro-apoptotic genes Bak1 and Klf13 in CMs (Figure D). In conclusion, these findings reveal a pivotal role for miR-125b-5p in regulating CM survival during acute myocardial infarction.