Novel pan-ERR agonists ameliorate heart failure through enhancing cardiac fatty acid metabolism and mitochondrial function

Cardiac metabolic dysfunction is a hallmark of heart failure. Estrogen related receptors ERRalpha and ERRgamma are essential regulators of cardiac metabolism. Therefore, activation of ERR could be a potential theraputic intervention for heart failure. However, in vivo studies demonstrating the potential utility of ERR agonists for heart failure treatment are lacking, as compounds with pharmackinetics appropriate for in vivo use have not been available. Using a structure-based design approach, we designed and synthesized two structurally distinct pan-ERR agonists, SLU-PP-332 (332) and SLU-PP-915 (915), which significantly improved ejection fraction, ameliorated fibrosis and increased survival associated with pressure overload-induced heart failure without affecting cardiac hypertrophy. Mechanistically, a broad spectrum of metabolic genes was transcriptionally activated by ERR agonists, particulary genes involved in fatty acid metabolism and mitochondrial function. Using both in vitro and in vivo genetic dependency experiments, we show that ERRgamma is the main mediatorof ERR agonism-induced transcriptional regulation and cardioprotection and definitively demonstrated target specificity. Additionally, ERR agonism also led to downregulation of cell cycle and development pathways, which was partially mediated by E2F1 in cardiomyocyte. In summary, ERR agonists maintain oxidative metabolism, which confers cardiac protection against pressure overload-induced heart failure in vivo. Our results provide direct pharmacological evidence supporting the further in vivo development of ERR agonists as novel heart failure theraputics. Overall design: To investigate ERR dependency in response to pan-ERR agonist 915, we used siRNA-targeted knockdown of ERRalpha and ERRgamma in neonatal rat ventricular myocytes (NRVM). As a control for the double-knockdown (DKD) NRVM we generated NRVM with non-targeting scramble siRNA (S). Gene expression of DKD and S lines were assessed when treated with 915 or vehicle control. To investigate the effect of ERR agonist 332 on cardiac function in a pressure-overload model, we performed TAC or sham surgery and treated mice with 332 (IP injection) for 6 weeks following surgery.