Abstract 9682: The Cardiac Protective Effects of Novel Synthetic Pan-Estrogen Related Receptor Agonists Slu-pp-332 and Slu-pp-915

• Published in: Circulation (New York, N.Y.) N.Y.), 2021-11, Vol.144 (Suppl_1), p.A9682-A9682
• Main Authors: Xu, Weiyi, Billon, Cyrielle, Li, Hui, Nasiotis, Eleni, Fu, Chen, Pei, Liming, Wynshaw-Boris, Anthony, Burris, Thomas P, Zhang, Lilei
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.144.suppl_1.9682

IntroductionEstrogen receptor-related orphan receptors ERRα and ERRγ are essential regulators for cardiac metabolism. Mice lacking ERRα and ERRγ develops lethal cardiomyopathy and heart failure. Therefore, activation of ERR is a potential therapeutic intervention for HF treatment. However, no natural or synthetic ERR agonist is available to demonstrate their pharmacological effect in vivo. HypothesisERR agonist can provide cardioprotection against heart failure. MethodsTwo structurally distinct pan-ERR agonists, SLU-PP-332 (332) and SLU-PP-915 (915) were chemically synthesized. Transaortic constriction (TAC) was performed to induce heart failure in adult male mice. Cardiac function was assessed by echocardiography. Wheat germ agglutinin (WGA) staining was perform on cardiac muscle sections. In vitro study was performed in neonatal rat ventricular myocytes (NRVMs). Results332 treatment significantly improved ejection fraction and mitochondrial ultrastructure, and reduced the expression of Nppa/Nppb and cardiac fibrosis in mice after 6-week TAC. Consistently, 915 treatment also greatly improved cardiac function in vivo. However, echocardiography and WGA staining showed that 332/915 failed to prevent cardiac hypertrophy in mouse after 6-week TAC. Moreover, 332/915 did not prevent the cardiomyocyte hypertrophy as well as activation of ERK1/2 and NFAT signaling pathways in NRVMs treated with phenylephrine. Further analysis using transcriptomics and metabolomics approaches revealed that 332/915 upregulated oxidative phosphorylation and fatty acid metabolism pathway in vitro. In addition, 332/915 induced downregulation of cell cycle genes in vitro, which was partially mediated by E2F1. Finally, interrogation of ERR dependency showed that siRNA knockdown of ERRγ, but not ERRα or ERRβ, abolished most of the 332/915-induced transcriptions of metabolic genes in vitro. Conclusions332/915, mainly through ERRγ, elevate mitochondrial function and fatty acid metabolism leading to improved cardiac function in TAC-induced heart failure, suggesting ERR agonist holds potential as a heart failure therapeutic agent.