BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection.
Cell
; 184(8): 2167-2182.e22, 2021 04 15.
Article
en En
| MEDLINE
| ID: mdl-33811809
ABSTRACT
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 1ß, and poly(IC), 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.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Factores de Transcripción
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Cardiotónicos
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Proteínas de Ciclo Celular
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Quinazolinonas
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COVID-19
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Cardiopatías
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
Idioma:
En
Revista:
Cell
Año:
2021
Tipo del documento:
Article