Author: 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
Title: Bromodomain and Extraterminal Inhibition Blocks Inflammation-Induced Cardiac Dysfunction and SARS-CoV-2 Infection (Pre-Clinical) Cord-id: cu5mq6qc Document date: 2021_2_15
ID: cu5mq6qc
Snippet: 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 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 dias
Document: 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 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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