Proteomics

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Discovery of drugs to treat cytokine storm-induced cardiac dysfunction


ABSTRACT: SARS-CoV2 infection leads to cardiac injury and dysfunction in 20-30% of hospitalized patients and higher rates of mortality in patients with pre-existing cardiovascular disease. Inflammatory factors released as part of the 'cytokine storm' are thought to play a critical role in cardiac dysfunction in severe COVID-19 patients. Here we use human cardiac organoid technology combined with high sensitivity phosphoproteomics and single nuclei RNA sequencing to identify inflammatory targets inducing cardiac dysfunction. This new pipeline allowed rapid progress and identification of putative therapeutics. We identify a novel interferon-gamma driven BRD4 (bromodomain protein 4)-fibrosis/iNOS axis as a key intracellular mediator of inflammation-induced cardiac dysfunction. This axis is therapeutically targetable using BRD4 inhibitors, which promoted full recovery of function in human cardiac organoids and prevented severe inflammation and death in a cytokine-storm mouse model. The BRD inhibitor INCB054329 was the most efficacious, and is a prime candidate for drug repurposing to attenuate cardiac dysfunction and improve COVID-19 mortality in humans.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Heart

DISEASE(S): Covid-19

SUBMITTER: Sean Humphrey  

LAB HEAD: Sean Humphrey

PROVIDER: PXD020994 | Pride | 2022-02-21

REPOSITORIES: Pride

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Publications

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

Mills Richard J RJ   Humphrey Sean J SJ   Fortuna Patrick R J PRJ   Lor Mary M   Foster Simon R SR   Quaife-Ryan Gregory A GA   Johnston Rebecca L RL   Dumenil Troy T   Bishop Cameron C   Rudraraju Rajeev R   Rawle Daniel J DJ   Le Thuy T   Zhao Wei W   Lee Leo L   Mackenzie-Kludas Charley C   Mehdiabadi Neda R NR   Halliday Christopher C   Gilham Dean D   Fu Li L   Nicholls Stephen J SJ   Johansson Jan J   Sweeney Michael M   Wong Norman C W NCW   Kulikowski Ewelina E   Sokolowski Kamil A KA   Tse Brian W C BWC   Devilée Lynn L   Voges Holly K HK   Reynolds Liam T LT   Krumeich Sophie S   Mathieson Ellen E   Abu-Bonsrah Dad D   Karavendzas Kathy K   Griffen Brendan B   Titmarsh Drew D   Elliott David A DA   McMahon James J   Suhrbier Andreas A   Subbarao Kanta K   Porrello Enzo R ER   Smyth Mark J MJ   Engwerda Christian R CR   MacDonald Kelli P A KPA   Bald Tobias T   James David E DE   Hudson James E JE  

Cell 20210316 8


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 d  ...[more]

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