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

First Author  Mills RJ Year  2021
Journal  Cell Volume  184
Issue  8 Pages  2167-2182.e22
PubMed ID  33811809 Mgi Jnum  J:335894
Mgi Id  MGI:6706306 Doi  10.1016/j.cell.2021.03.026
Citation  Mills RJ, et al. (2021) BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection. Cell 184(8):2167-2182.e22
abstractText  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 1beta, 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.
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