Abstract 293: MicroRNA-125b-5p Protect the Mouse Heart from Ischemic Injury 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. For example, miR-125a is up-regulated in patients with heart failure (HF), while miR-125b is down-regulated in patients with end-stage dilated cardiomyopathy (DCM) and ischemic DCM. Circulating levels of these two miRs have been recently proposed as potential biomarkers of HF. We previously showed that β1-adrenergic receptor-mediated cardioprotective signaling through β-arrestin1 stimulates the processing of miR-125a and miR-125b in mouse heart (Figure A-C). Here, we hypothesize that these two miRs might confer cardioprotection against ischemic injury. Using cultured cardiomyocyte (CM) and in vivo approaches, we show that these miRs are ischemic stress-responsive protectors against CM apoptosis. CMs lacking miR-125a or miR-125b have an increased sensitivity to stress-induced apoptosis, while CMs overexpressing miR-125a or miR-125b have increased phospho-AKT pro-survival signaling. Moreover, we demonstrate that loss-of-function of miR-125b in mouse heart causes abnormalities in cardiac structure and function after myocardial infarction. The cardioprotective roles of the two miRs during ischemic injury are in part attributed to direct repression of the pro-apoptotic genes Bak1 and Klf13 in CMs (Figure D). In conclusion, these findings reveal pivotal roles for miR-125a and miR-125b as important regulators of CM survival during cardiac injury.