BET Inhibition Blocks Inflammation-Induced Cardiac Dysfunction and SARS-CoV-2 Infection
Type
ArticleAuthor/s
Mills, Richard J.Humphrey, Sean J.
Fortuna, Patrick RJ.
Lor, Mary
Foster, Simon R.
Quaife-Ryan, Gregory A.
Johnston, Rebecca L.
Dumenil, Troy
Bishop, Cameron
Ruraraju, 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 PA.
Bald, Tobias
James, David E.
Hudson, James E.
Abstract
Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined, but could be direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline ...
See moreCardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined, but could be 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 and hearts of SARS-CoV-2 infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCO 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 FDA breakthrough designated drug apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage.
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See moreCardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined, but could be 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 and hearts of SARS-CoV-2 infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCO 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 FDA breakthrough designated drug apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage.
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Date
2021Share