Bromodomain Inhibition Blocks Inflammation-Induced Cardiac Dysfunction and SARS-CoV2 Infection in Pre-Clinical Models
Mills, R. J.; Humphrey, S. J.; Fortuna, P. R.; Quaife-Ryan, G. A.; Lor, M.; Ruraraju, R.; Rawle, D. J.; Le, T.; Zhao, W.; Lee, L.; Mackenzie-Kludas, C.; Mehdiabadi, N. R.; Devilee, L.; Voges, H. K.; Reynolds, L. T.; Krumeich, S.; Mathieson, E.; Abu-Bonsrah, D.; Karavendzas, K.; Griffen, B.; Titmarsh, D. M.; Elliott, D. A.; McMahon, J. H.; Suhrbier, A.; Subbarao, K.; Porrello, E. R.; Smyth, M. J.; Engwerda, C. R.; MacDonald, K. P.; Bald, T.; James, D. E.; Hudson, J. E.
10.1101/2020.08.23.258574 bioRxivShow 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 combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory cytokine-storm, a cocktail of interferon gamma, interleukin 1{beta} 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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