心力衰竭
压力过载
兴奋剂
药理学
β氧化
心功能曲线
化学
下调和上调
线粒体
内分泌学
内科学
受体
生物
医学
新陈代谢
生物化学
心肌肥大
基因
作者
Weiyi Xu,Cyrielle Billon,Hui Li,Matthew Hayes,Keyang Yu,McKenna Losby,Carissa S. Hampton,Christiana M. Adeyemi,Andrea Graves,Eleni Nasiotis,Chen Fu,Ryan D. Welch,Ronald M. Evans,Liming Pei,John K. Walker,Aleksandar Milosavljevic,Thomas P. Burris,Lilei Zhang
标识
DOI:10.1101/2022.02.14.480431
摘要
Abstract Cardiac metabolic dysfunction is a hallmark of heart failure. Estrogen related receptors ERRα and ERRγ are essential regulators for cardiac metabolism. Therefore, activation of ERR could be a potential therapeutic intervention for heart failure. However, no natural or synthetic ERR agonist is available to demonstrate their pharmacological effect in vivo . 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 and ameliorated fibrosis against pressure overload-induced heart failure without affecting cardiac hypertrophy. Mechanistically, a broad-spectrum of metabolic genes were transcriptionally activated by ERR agonists, particularly genes involved in fatty acid metabolism and mitochondrial function, which were mainly mediated by ERRγ. Metabolomics analysis showed significant normalization of metabolic profiles in fatty acid/lipid and TCA/OXPHOS metabolites by 915 in the mouse heart with 6-week pressure overload. Autophagy was also induced by ERR agonists in cardiomycoyte. On the other hand, ERR agonism 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 provided direct pharmacological evidence supporting the further development of ERR agonists as novel heart failure therapeutics in vivo .
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