Abstract P3042: Cardiomyocyte MicroRNA-125a-5p Plays A Vital Protective Role In Myocardial Infarction And Directly Represses Proapoptotic GTP-Cyclohydrolase I Feedback Regulator

Abstract

Background: We reported that microRNA-125a-5p (miR-125a) is activated by β-blocker carvedilol acting through β-arrestin1-mediated β1-adrenergic receptor (receptor found mainly in cardiomyocytes [CMs]) signaling (Figure A). GTP cyclohydrolase I feedback regulator (GCHFR) inhibits tetrahydrobiopterin which is protective in myocardial infarction (MI). Despite these findings, the roles of miR-125a and GCHFR in MI and their mechanisms of actions remain elusive. Here, we hypothesize that miR-125a in CMs plays a protective role in MI in part by repressing GCHFR, a novel target of miR-125a. Methods and Results: Fractionation of cardiac cell types isolated from mouse hearts reveals that miR-125a expression is higher in CMs than other cells. Using cultured CM and in vivo approaches, we show that miR-125a is an ischemic stress-responsive protector against CM apoptosis. CMs lacking miR-125a exhibit an increased sensitivity to apoptosis, whereas CMs overexpressing miR-125a have increased phospho-AKT prosurvival signaling. MiR-125a is downregulated in failing hearts, and miR-125a overexpression protects mouse hearts against MI. Systemic deletion of miR-125a in mice worsens maladaptive post-MI remodeling. Genome-wide profiling in miR-125a KO mouse hearts identifies GCHFR as a novel target of miR-125a. Mechanistically, protective roles of miR-125a in CMs are in part attributed to the direct and functional repression of proapoptotic GCHFR. Last, novel conditional CM-specific miR-125a KO in mice exacerbates maladaptive cardiac remodeling after MI (Figure B). Conclusions: Our findings suggest a crucial role for the miR-125a/GCHFR axis in regulating CM survival post-MI.