Abstract 11967: Microrna-150 Overexpression Blunts Maladaptive Cardiac Remodeling in Mice With Cardiomyocyte-Specific Loss of β-Arrestin-Mediated β 1 -Adrenergic Receptor Signaling

Abstract

Background and Aims: β-arrestins transduce alternative pathways independent of G protein signaling, a concept known as β-arrestin-biased signaling that is promoted by G protein-coupled receptor kinase (GRK) 5/6 phosphorylation on β-adrenergic receptors (βARs). The β 1 AR is found primarily in the heart (mainly in cardiomyocytes [CMs]) and β-arrestin-mediated β 1 AR signaling elicits cardioprotection by CM survival. We showed that a small noncoding RNA (ncRNA), microRNA-150 (miR-150) is upregulated by the β-blocker carvedilol acting through β-arrestin-mediated β 1 AR signaling, and that CM miR-150 confers cardioprotection (see Figure). Here, we investigate if miR-150 in part rescues maladaptive cardiac remodeling seen in mice with CM-specific abrogation of β-arrestin-mediated β 1 AR signaling. Methods and Results: Using CM-specific transgenic (TG) mice expressing a mutant β 1 AR (i.e. GRK - β 1 AR exhibiting impairment in β-arrestin-mediated β 1 AR signaling and miR-150 activation by carvedilol), we first develop a novel double TG (DTG) mouse line overexpressing miR-150 and CM-specific GRK - β 1 AR. We demonstrate that miR-150 improves maladaptive cardiac remodeling observed in CM-specific GRK - β 1 AR TG mice after chronic catecholamine stimulation. Genome-wide circular RNA, long ncRNA (lncRNA) and mRNA profiling analyses in DTG mouse hearts unveil a subset of cardiac ncRNAs and genes as heretofore unrecognized mechanisms for miR-150’s beneficial effects. We further show that lncRNA Gm41664 and Gdap1l1 have miR-150 binding sites, and that they are direct novel upstream and downstream regulators of miR-150. Lastly, protective roles of miR-150 in CMs are in part attributed to the functional repression of pro-apoptotic Gdap1l1 and are mitigated by pro-apoptotic Gm41664 (see Figure). Conclusions: Our findings support that miR-150 contributes significantly to β 1 AR/β-arrestin-mediated cardioprotection by regulating a unique ncRNA and gene signature in CMs.