BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection
Authors:
- Mills, Richard J.
- Humphrey, Sean J.
- Fortuna, Patrick R.J.
- Lor, Mary
- Foster, Simon R.
- Quaife-Ryan, Gregory A.
- Johnston, Rebecca L.
- Dumenil, Troy
- Bishop, Cameron
- Rudraraju, Rajeev
- Rawle, Daniel J.
- Le, Thuy
- Zhao, Wei
- Lee, Leo
- Mackenzie-Kludas, Charley
- Mehdiabadi, Neda R.
- Halliday, Christopher
- Gilham, Dean
- Fu, Li
- Nicholls, Stephen J.
- Johansson, Jan
- Sweeney, Michael
- Wong, Norman C.W.
- Kulikowski, Ewelina
- Sokolowski, Kamil A.
- Tse, Brian W.C.
- Devilée, Lynn
- Voges, Holly K.
- Reynolds, Liam T.
- Krumeich, Sophie
- Mathieson, Ellen
- Abu-Bonsrah, Dad
- Karavendzas, Kathy
- Griffen, Brendan
- Titmarsh, Drew
- Elliott, David A.
- McMahon, James
- Suhrbier, Andreas
- Subbarao, Kanta
- Porrello, Enzo R.
- Smyth, Mark J.
- Engwerda, Christian R.
- MacDonald, Kelli P.A.
- Bald, Tobias
- James, David E.
- Hudson, James E.
Details:
Cell, Volume 184, Issue 8, 2021-04-15
Article Link: Click here
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.