| Autor: |
Christopher Halliday, Kamil A. Sokolowski, Sophie Krumeich, David A. Elliott, Lynn Devilee, Sean J. Humphrey, Tobias Bald, Brian W.C. Tse, Gregory A. Quaife-Ryan, Leo J. Lee, Mark J. Smyth, David E. James, Rebecca L Johnston, Kanta Subbarao, Holly K. Voges, Richard J. Mills, Michael O. Sweeney, Liam T Reynolds, Stephen J. Nicholls, Mary Lor, Charley Mackenzie-Kludas, Li Fu, Jan Johansson, Kelli P. A. MacDonald, Partrick Rj Fortuna, Troy Dumenil, Norman C.W. Wong, Daniel J. Rawle, Brendan Griffen, Dad Abu-Bonsrah, Ellen Mathieson, Kathy Karavendzas, Neda R Mehdiabadi, Christian R. Engwerda, James E. Hudson, Rajeev Ruraraju, Dean Gilham, Andreas Suhrbier, Wei Zhao, Ewelina Kulikowski, Enzo R. Porrello, Simon R. Foster, Drew M. Titmarsh, Cameron Bishop, James H McMahon, Thuy T. Le |
| Rok vydání: |
2020 |
| Předmět: |
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| DOI: |
10.1101/2020.08.23.258574 |
| Popis: |
SUMMARYCardiac 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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