REV-ERBa Ameliorates Heart Failure Through Transcription Repression

Heart failure remains a major unmet clinical need and current therapies targeting neurohomonal and hemodynamic regulation have limited efficacy. We report that pharmacological activation of the transcriptional repressor REV-ERBa prevents expression of a pathological gene program and cardiomyocyte hypertrophy. In vivo, REV-ERBa agonism prevents development and halts progression of heart failure in mouse models. Thus, modulation of gene networks by targeting REV-ERBa represents a novel approach to heart failure therapy. Overall design: We performed RNAseq on NRVM at baseline and after PE stimulation (4 hr and 48 hr) in the presence or absence of SR9009 (SR or Veh were given 24 hr prior to PE).

心力衰竭仍是亟待解决的重大临床需求，当前针对神经激素及血流动力学调控的治疗方案疗效有限。本研究证实，转录抑制因子REV-ERBa的药理学激活可阻断病理性基因程序的表达与心肌细胞肥大。在体实验中，REV-ERBa激动剂可阻止小鼠心力衰竭模型的疾病发生并阻断病情进展。因此，以REV-ERBa为靶点调控基因网络，代表了心力衰竭治疗的全新策略。

实验设计概况：我们对新生大鼠心室肌细胞（NRVM）在基线状态、苯肾上腺素（PE）刺激4小时及48小时后进行了RNA测序，实验设置了提前24小时给予SR9009（SR）或溶剂（Veh）预处理的组别。