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BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection.
Mills, Richard J; Humphrey, Sean J; Fortuna, Patrick R J; Lor, Mary; Foster, Simon R; Quaife-Ryan, Gregory A; Johnston, Rebecca L; Dumenil, Troy; Bishop, Cameron; Rudraraju, Rajeev; Rawle, Daniel J; Le, Thuy; Zhao, Wei; Lee, Leo; Mackenzie-Kludas, Charley; Mehdiabadi, Neda R; Halliday, Christopher; Gilham, Dean; Fu, Li; Nicholls, Stephen J; Johansson, Jan; Sweeney, Michael; Wong, Norman C W; Kulikowski, Ewelina; Sokolowski, Kamil A; Tse, Brian W C; Devilée, Lynn; Voges, Holly K; Reynolds, Liam T; Krumeich, Sophie; Mathieson, Ellen; Abu-Bonsrah, Dad; Karavendzas, Kathy; Griffen, Brendan; Titmarsh, Drew; Elliott, David A; McMahon, James; Suhrbier, Andreas; Subbarao, Kanta; Porrello, Enzo R; Smyth, Mark J; Engwerda, Christian R; MacDonald, Kelli P A; Bald, Tobias; James, David E; Hudson, James E.
  • 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 Infect
  • 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.
Cell ; 184(8): 2167-2182.e22, 2021 04 15.
Article in English | MEDLINE | ID: covidwho-1135274
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 1ß, and poly(IC), 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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Transcription Factors / Cardiotonic Agents / Cell Cycle Proteins / Quinazolinones / COVID-19 / Heart Diseases Type of study: Prognostic study Topics: Long Covid Limits: Animals / Female / Humans Language: English Journal: Cell Year: 2021 Document Type: Article Affiliation country: J.cell.2021.03.026

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Transcription Factors / Cardiotonic Agents / Cell Cycle Proteins / Quinazolinones / COVID-19 / Heart Diseases Type of study: Prognostic study Topics: Long Covid Limits: Animals / Female / Humans Language: English Journal: Cell Year: 2021 Document Type: Article Affiliation country: J.cell.2021.03.026