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

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.

• Authors: 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 Rudraraju, Daniel J Rawle, Thuy Le, Wei Zhao, Leo Lee, Charley Mackenzie-Kludas, Neda R Mehdiabadi, Christopher Halliday, Dean Gilham, Li Fu, Stephen J Nicholls, Jan Johansson, Michael Sweeney, Norman C W Wong, Ewelina Kulikowski, Kamil A Sokolowski, Brian W C Tse, Lynn Devilée, Holly K Voges, Liam T Reynolds, Sophie Krumeich, Ellen Mathieson, Dad Abu-Bonsrah, Kathy Karavendzas, Brendan Griffen, Drew Titmarsh, David A Elliott, James 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
• Journal: Cell (Cell) Vol. 184 Issue 8 Pg. 2167-2182.e22 (04 15 2021) ISSN: 1097-4172 [Electronic] United States
• PMID: 33811809 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

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

Topics

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