1. Academic Validation
  2. BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection

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.
Richard J Mills 1 Sean J Humphrey 2 Patrick R J Fortuna 1 Mary Lor 1 Simon R Foster 1 Gregory A Quaife-Ryan 1 Rebecca L Johnston 1 Troy Dumenil 1 Cameron Bishop 1 Rajeev Rudraraju 3 Daniel J Rawle 1 Thuy Le 1 Wei Zhao 4 Leo Lee 4 Charley Mackenzie-Kludas 4 Neda R Mehdiabadi 5 Christopher Halliday 6 Dean Gilham 6 Li Fu 6 Stephen J Nicholls 7 Jan Johansson 8 Michael Sweeney 8 Norman C W Wong 6 Ewelina Kulikowski 6 Kamil A Sokolowski 9 Brian W C Tse 9 Lynn Devilée 1 Holly K Voges 1 Liam T Reynolds 1 Sophie Krumeich 1 Ellen Mathieson 1 Dad Abu-Bonsrah 10 Kathy Karavendzas 5 Brendan Griffen 11 Drew Titmarsh 11 David A Elliott 5 James McMahon 12 Andreas Suhrbier 13 Kanta Subbarao 14 Enzo R Porrello 15 Mark J Smyth 1 Christian R Engwerda 1 Kelli P A MacDonald 1 Tobias Bald 16 David E James 17 James E Hudson 18
Affiliations

Affiliations

  • 1 QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia.
  • 2 Charles Perkins Centre, School of Life and Environmental Science, The University of Sydney, Sydney 2006, NSW, Australia.
  • 3 The WHO Collaborating Centre for Reference and Research on Influenza, The Peter Doherty Institute for Infection and Immunity, Melbourne 3000, VIC, Australia; Department of Microbiology and Immunology, The University of Melbourne, Melbourne 3052, VIC, Australia; The Peter Doherty Institute for Infection and Immunity, Melbourne 3000, VIC, Australia.
  • 4 The Peter Doherty Institute for Infection and Immunity, Melbourne 3000, VIC, Australia.
  • 5 Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne 3052, VIC, Australia.
  • 6 Resverlogix Corp., Calgary T3E 6L1, AB, Canada.
  • 7 Victorian Heart Hospital, Monash University, Clayton 3168, VIC, Australia.
  • 8 Resverlogix Corp., San Francisco, CA 94104, USA.
  • 9 Preclinical Imaging Facility, Translational Research Institute, Brisbane, QLD, Australia.
  • 10 Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne 3052, VIC, Australia; Department of Paediatrics, The University of Melbourne, Melbourne 3052, VIC, Australia.
  • 11 Dynomics Inc., San Mateo, CA 94401, USA; Dynomics Pty Ltd, Brisbane 4000, QLD, Australia.
  • 12 Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne 3004, VIC, Australia; Department of Infectious Diseases, Monash Medical Centre, Clayton 3168, VIC, Australia.
  • 13 QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia; GVN Center of Excellence, Australian Infectious Diseases Research Centre, Brisbane, QLD, Australia.
  • 14 The WHO Collaborating Centre for Reference and Research on Influenza, The Peter Doherty Institute for Infection and Immunity, Melbourne 3000, VIC, Australia; The Peter Doherty Institute for Infection and Immunity, Melbourne 3000, VIC, Australia.
  • 15 Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne 3052, VIC, Australia; Department of Physiology, School of Biomedical Sciences, The University of Melbourne, Melbourne 3052, VIC, Australia.
  • 16 QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia; Institute of Experimental Oncology, University Hospital Bonn, Bonn 53127, Germany.
  • 17 Charles Perkins Centre, School of Life and Environmental Science, The University of Sydney, Sydney 2006, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney 2006, NSW, Australia.
  • 18 QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia. Electronic address: [email protected].
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.

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