REV-ERBα ameliorates heart failure through transcription repression

JCI Insight. 2017 Sep 7;2(17):e95177. doi: 10.1172/jci.insight.95177.


A cure for heart failure remains a major unmet clinical need, and current therapies targeting neurohomonal and hemodynamic regulation have limited efficacy. The pathological remodeling of the myocardium has been associated with a stereotypical gene expression program, which had long been viewed as the consequence and not the driver of the disease until very recently. Despite the advance, there is no therapy available to reverse the already committed gene program. Here, we demonstrate that transcriptional repressor REV-ERB binds near driver transcription factors across the genome. Pharmacological activation of REV-ERB selectively suppresses aberrant pathologic gene expression and prevents cardiomyocyte hypertrophy. In vivo, REV-ERBα activation prevents development of cardiac hypertrophy, reduces fibrosis, and halts progression of advanced heart failure in mouse models. Thus, to our knowledge, modulation of gene networks by targeting REV-ERBα represents a novel approach to heart failure therapy.

Keywords: Cardiology; Cardiovascular disease; Heart failure.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cardiotonic Agents / pharmacology
  • Gene Expression
  • Gene Regulatory Networks
  • Heart Failure / genetics
  • Heart Failure / prevention & control*
  • Humans
  • Hypertrophy / chemically induced
  • Male
  • Mice, Inbred C57BL
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / physiology*
  • Phenylephrine / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Transcription, Genetic*


  • Cardiotonic Agents
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • Phenylephrine