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

Richard J. Mills, Sean J. Humphrey, Patrick R.J. Fortuna, Mary Lor, Simon R. Foster, Gregory A Quaife-Ryan, Rebecca L. Johnston, Troy Dumenil, Cameron Bishop, Rajeev Ruraraju, Daniel J. Rawle, Thuy Le, Wei Zhao, Leo Lee, Charley MacKenzie-Kludas, Neda R. Mehdiabadi, Chris Halliday, Dean Gilham, Li Fu, Stephen J. NichollsJan O. Johansson, Michael Sweeney, Norman C.W. Wong, Ewelina Kulikowski, Kamil A. Sokolowski, Brian W.C. Tse, Lynn Devilée, Holly K. Voges, Sophie Krumeich, Liam T. Reynolds, Ellen Mathieson, Dad Abu-Bonsrah, Kathy Karavendzas, Brendan Griffen, Drew Titmarsh, David Elliott, James H. McMahon, Andreas Suhrbier, Kanta Subbarao , Enzo R. Porrello, Mark J. Smyth, Christian R. Engwerda, Kelli P.A. MacDonald, Tobias Bald, David E. James, James E. Hudson

Research output: Contribution to journalArticleResearchpeer-review

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2167-2182.e22
Number of pages38
JournalCell
Volume184
Issue number8
DOIs
Publication statusPublished - 15 Apr 2021

Keywords

  • Bromodomain and extraterminal family inhibitors
  • COVID-19
  • drug discovery
  • heart
  • inflammation
  • organoids

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