BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection

Cell. 2021 Apr 15;184(8):2167-2182.e22. doi: 10.1016/j.cell.2021.03.026. Epub 2021 Mar 16.

Abstract

Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined but could be through direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory "cytokine-storm", a cocktail of interferon gamma, interleukin 1β, and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids (hCOs) and hearts of SARS-CoV-2-infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCOs and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression, and reduces SARS-CoV-2 infection of cardiomyocytes. Together, BETi, including the Food and Drug Administration (FDA) breakthrough designated drug, apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage.

Keywords: Bromodomain and extraterminal family inhibitors; COVID-19; drug discovery; heart; inflammation; organoids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2 / metabolism
  • Animals
  • COVID-19 / complications*
  • COVID-19 Drug Treatment
  • Cardiotonic Agents / therapeutic use*
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Cytokines / metabolism
  • Female
  • Heart Diseases / drug therapy*
  • Heart Diseases / etiology
  • Human Embryonic Stem Cells
  • Humans
  • Inflammation / complications
  • Inflammation / drug therapy
  • Mice
  • Mice, Inbred C57BL
  • Quinazolinones / therapeutic use*
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / metabolism

Substances

  • BRD4 protein, human
  • Cardiotonic Agents
  • Cell Cycle Proteins
  • Cytokines
  • Quinazolinones
  • Transcription Factors
  • apabetalone
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2