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

Autor:	Mills RJ; QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia., Humphrey SJ; Charles Perkins Centre, School of Life and Environmental Science, The University of Sydney, Sydney 2006, NSW, Australia., Fortuna PRJ; QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia., Lor M; QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia., Foster SR; QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia., Quaife-Ryan GA; QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia., Johnston RL; QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia., Dumenil T; QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia., Bishop C; QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia., Rudraraju R; The WHO Collaborating Centre for Reference and Research on Influenza, The Peter Doherty Institute for Infection and Immunity, Melbourne 3000, VIC, Australia; Department of Microbiology and Immunology, The University of Melbourne, Melbourne 3052, VIC, Australia; The Peter Doherty Institute for Infection and Immunity, Melbourne 3000, VIC, Australia., Rawle DJ; QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia., Le T; QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia., Zhao W; The Peter Doherty Institute for Infection and Immunity, Melbourne 3000, VIC, Australia., Lee L; The Peter Doherty Institute for Infection and Immunity, Melbourne 3000, VIC, Australia., Mackenzie-Kludas C; The Peter Doherty Institute for Infection and Immunity, Melbourne 3000, VIC, Australia., Mehdiabadi NR; Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne 3052, VIC, Australia., Halliday C; Resverlogix Corp., Calgary T3E 6L1, AB, Canada., Gilham D; Resverlogix Corp., Calgary T3E 6L1, AB, Canada., Fu L; Resverlogix Corp., Calgary T3E 6L1, AB, Canada., Nicholls SJ; Victorian Heart Hospital, Monash University, Clayton 3168, VIC, Australia., Johansson J; Resverlogix Corp., San Francisco, CA 94104, USA., Sweeney M; Resverlogix Corp., San Francisco, CA 94104, USA., Wong NCW; Resverlogix Corp., Calgary T3E 6L1, AB, Canada., Kulikowski E; Resverlogix Corp., Calgary T3E 6L1, AB, Canada., Sokolowski KA; Preclinical Imaging Facility, Translational Research Institute, Brisbane, QLD, Australia., Tse BWC; Preclinical Imaging Facility, Translational Research Institute, Brisbane, QLD, Australia., Devilée L; QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia., Voges HK; QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia., Reynolds LT; QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia., Krumeich S; QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia., Mathieson E; QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia., Abu-Bonsrah D; Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne 3052, VIC, Australia; Department of Paediatrics, The University of Melbourne, Melbourne 3052, VIC, Australia., Karavendzas K; Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne 3052, VIC, Australia., Griffen B; Dynomics Inc., San Mateo, CA 94401, USA; Dynomics Pty Ltd, Brisbane 4000, QLD, Australia., Titmarsh D; Dynomics Inc., San Mateo, CA 94401, USA; Dynomics Pty Ltd, Brisbane 4000, QLD, Australia., Elliott DA; Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne 3052, VIC, Australia., McMahon J; Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne 3004, VIC, Australia; Department of Infectious Diseases, Monash Medical Centre, Clayton 3168, VIC, Australia., Suhrbier A; QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia; GVN Center of Excellence, Australian Infectious Diseases Research Centre, Brisbane, QLD, Australia., Subbarao K; The WHO Collaborating Centre for Reference and Research on Influenza, The Peter Doherty Institute for Infection and Immunity, Melbourne 3000, VIC, Australia; The Peter Doherty Institute for Infection and Immunity, Melbourne 3000, VIC, Australia., Porrello ER; Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne 3052, VIC, Australia; Department of Physiology, School of Biomedical Sciences, The University of Melbourne, Melbourne 3052, VIC, Australia., Smyth MJ; QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia., Engwerda CR; QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia., MacDonald KPA; QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia., Bald T; QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia; Institute of Experimental Oncology, University Hospital Bonn, Bonn 53127, Germany., James DE; Charles Perkins Centre, School of Life and Environmental Science, The University of Sydney, Sydney 2006, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney 2006, NSW, Australia., Hudson JE; QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia. Electronic address: james.hudson@qimrberghofer.edu.au.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2021 Apr 15; Vol. 184 (8), pp. 2167-2182.e22. Date of Electronic Publication: 2021 Mar 16.
DOI:	10.1016/j.cell.2021.03.026
Abstrakt:	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. Competing Interests: Declaration of interests R.J.M., J.E.H., G.A.Q.-R., D.M.T., and E.R.P. are co-inventors on patents relating to cardiac organoid maturation and cardiac therapeutics. J.E.H. is co-inventor on licensed patents for engineered heart muscle. R.J.M., E.R.P., D.M.T., B.G., and J.E.H. are co-founders, scientific advisors, and stockholders in Dynomics. D.M.T. and B.G. are employees of Dynomics. C.H., D.G., L.F., J.J., M.S., N.C.W.W., and E.K. are employees of Resverlogix. S.J.N. received honoraria and research support from Resverlogix. QIMR Berghofer Medical Research Institute filed a patent on the use of BETi. (Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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