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BET Inhibition Blocks Inflammation-Induced Cardiac Dysfunction and SARS-CoV-2 Infection
- Source :
- Cell
- Publication Year :
- 2021
-
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 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 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.<br />A combination of phosphoproteomics, drug screening and single-cell sequencing approaches identifies how cytokines elevated in COVID-19 patients drives cardiac dysfunction, with BET inhibitors serving as potential lead candidates decrease ACE2 cardiac expression and infection.
- Subjects :
- Cardiotonic Agents
Heart Diseases
Human Embryonic Stem Cells
Diastole
Inflammation
Cell Cycle Proteins
Pharmacology
General Biochemistry, Genetics and Molecular Biology
Article
Cell Line
03 medical and health sciences
Mice
0302 clinical medicine
medicine
Animals
Humans
Interferon gamma
STAT1
Transcription factor
030304 developmental biology
Quinazolinones
0303 health sciences
biology
COVID-19
COVID-19 Drug Treatment
Mice, Inbred C57BL
Coronavirus
Angiotensin-converting enzyme 2
biology.protein
Cytokines
Tumor necrosis factor alpha
Female
Angiotensin-Converting Enzyme 2
medicine.symptom
030217 neurology & neurosurgery
medicine.drug
Transcription Factors
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Cell
- Accession number :
- edsair.doi.dedup.....c8980f221c915141159a88aa5bcdc235