Unknown

Dataset Information

0

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


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 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 (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.

SUBMITTER: Mills RJ 

PROVIDER: S-EPMC7962543 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| PRJEB43658 | ENA
| S-SCDT-10_1038-S44318-024-00061-0 | biostudies-other
2021-05-18 | GSE166209 | GEO
| S-EPMC8008343 | biostudies-literature
| S-EPMC5263857 | biostudies-literature
| S-EPMC8391731 | biostudies-literature
| S-EPMC4107547 | biostudies-literature
| S-EPMC7836110 | biostudies-literature
| S-EPMC8820466 | biostudies-literature
2021-01-19 | GSE165025 | GEO