A Novel High-Throughput Screen Identifies Abemaciclib as a Potent Inducer of Physiologic Hypertrophy and Cardioprotection

Abstract

Physiologic cardiac hypertrophy (PhCH) is an adaptive process associated with endurance exercise training that enhances cardiac function and offers protection against heart failure (HF). However, translating PhCH into effective therapies has been hampered by a limited understanding of the underlying molecular signals. Here, we developed a novel high-throughput screen based on a key morphometric adaptation to PhCH, increased cardiomyocyte length, and then screened small molecule libraries to identify compounds that induced this conditioning event in rodent primary cardiomyocytes. The screen identified the CDK4/CDK6 inhibitor abemaciclib (LY2835219), a clinically prescribed anti-cancer agent, as a potent PhCH remodeling cue in both rodent cardiomyocytes and human iPSC-derived cardiomyocytes. siRNA-targeted inhibition of CDK4 expression phenocopied abemaciclib treatment in cardiomyocytes, confirming the necessity to suppress CDK4 as a general prerequisite for inducing PhCH. In addition, RNA sequencing and phosphoproteomic analysis of cardiomyocytes treated with abemaciclib revealed activation of the protein kinase A (PKA) and AMP-activated protein kinase (AMPK) cascades, consistent with the known metabolic enhancement described in PhCH-induced remodeling. Finally, we noted that in vivo administration of abemaciclib improved cardiac function at baseline and maintained cardiac performance even in the presence of pathologic remodeling signals. These findings identify abemaciclib as a first-in-class therapeutic agent capable of inducing PhCH and suggest suppressing CDK4/6 in general as an unanticipated means to limit pathologic hypertrophy and heart failure.