RT Journal Article
SR Electronic
T1 Bromodomain Inhibition Blocks Inflammation-Induced Cardiac Dysfunction and SARS-CoV2 Infection in Pre-Clinical Models
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.08.23.258574
DO 10.1101/2020.08.23.258574
A1 Richard J Mills
A1 Sean J Humphrey
A1 Patrick RJ Fortuna
A1 Gregory A Quaife-Ryan
A1 Mary Lor
A1 Rajeev Ruraraju
A1 Daniel J Rawle
A1 Thuy Le
A1 Wei Zhao
A1 Leo Lee
A1 Charley Mackenzie-Kludas
A1 Neda R Mehdiabadi
A1 Lynn Devilée
A1 Holly K Voges
A1 Liam T Reynolds
A1 Sophie Krumeich
A1 Ellen Mathieson
A1 Dad Abu-Bonsrah
A1 Kathy Karavendzas
A1 Brendan Griffen
A1 Drew Titmarsh
A1 David A Elliott
A1 James McMahon
A1 Andreas Suhrbier
A1 Kanta Subbarao
A1 Enzo R Porrello
A1 Mark J Smyth
A1 Christian R Engwerda
A1 Kelli PA MacDonald
A1 Tobias Bald
A1 David E James
A1 James E Hudson
YR 2020
UL http://biorxiv.org/content/early/2020/10/16/2020.08.23.258574.abstract
AB 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 ‘cytokine-storm’ induced dysfunction. To identify mechanisms and discover cardio-protective therapeutics, we use a state-of-the-art pipeline combining human cardiac organoids with high throughput phosphoproteomics and single nuclei RNA sequencing. We identify that ‘cytokine-storm’ induced diastolic dysfunction can be caused by a cocktail of interferon gamma, interleukin 1β and poly(I:C) and also human serum from COVID-19 patients. Bromodomain protein 4 (BRD4) is activated along with pathology driving fibrotic and induced nitric oxide synthase genes. BRD inhibitors fully recover function in hCO and completely prevent death in a cytokine-storm mouse model. BRD inhibition decreases transcription of multiple genes, including fibrotic, induced nitric oxide synthase and ACE2, and reduces cardiac infection from SARS-CoV2. Thus, BRD inhibitors are promising candidates to prevent COVID-19 mediated cardiac damage.Competing Interest StatementR.J.M., J.E.H., G.A.Q.-R., D.M.T. and E.R.P. are listed as co-inventors on pending patents held by The University of Queensland and QIMR Berghofer Medical Research Institute that relate to cardiac organoid maturation and putative cardiac regeneration therapeutics. J.E.H. is a co-inventor on licensed patents held by the University of Goettingen. R.J.M, E.R.P., D.M.T., B.G. and J.E.H. are co-founders, scientific advisors and stockholders in Dynomics Inc. D.M.T. and B.G. are employees of Dynomics Inc. /Dynomics Pty Ltd. QIMR Berghofer Medical Research Institute has filed a patent on the use of BRD inhibitors.