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BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection
Richard J Mills1, Sean J Humphrey2, Patrick R J Fortuna1
1QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia.
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.
Insights
COVID-19 causes cardiac injury via inflammation. Bromodomain and extraterminal family inhibitors (BETi) show promise in preventing heart dysfunction and death in models, offering potential therapeutic strategies.
Area of Science:
- Cardiology
- Virology
- Molecular Biology
Background:
- COVID-19 is linked to cardiac injury and mortality.
- Mechanisms include direct viral infection or inflammation-induced cardiac dysfunction.
- Identifying therapeutic targets is crucial for managing COVID-19's cardiac impact.
Purpose of the Study:
- To elucidate the mechanisms of COVID-19-induced cardiac dysfunction.
- To identify potential cardio-protective drugs against COVID-19.
Main Methods:
- Utilized human cardiac organoids (hCOs) and K18-hACE2 mouse models.
- Employed phosphoproteomics and single nuclei RNA sequencing.
- Investigated the effects of inflammatory stimuli and BET inhibitors.
Main Results:
- A "cytokine-storm" (interferon gamma, interleukin 1β, poly(I:C)) induced diastolic dysfunction.
- Bromodomain-containing protein 4 activation and a viral response were observed in hCOs and mouse models.
- BET inhibitors (BETi) restored cardiac function in hCOs and prevented mortality in mice.
- BETi reduced viral gene transcription, ACE2 expression, and cardiomyocyte infection.
Conclusions:
- BETi, including apabetalone, effectively counteract COVID-19-induced cardiac dysfunction and mortality.
- BETi represent promising therapeutic candidates for preventing cardiac damage in COVID-19 patients.
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