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Bromodomain and Extraterminal Inhibition Blocks Inflammation-Induced Cardiac Dysfunction and SARS-CoV-2 Infection (Pre-Clinical)
bioRxiv - Cell Biology Pub Date : 2021-02-15 , DOI: 10.1101/2020.08.23.258574
Richard J Mills , Sean J Humphrey , Patrick RJ Fortuna , Mary Lor , Simon R Foster , Gregory A Quaife-Ryan , Rebecca L. Johnston , Troy Dumenil , Cameron Bishop , Rajeev Ruraraju , Daniel J Rawle , Thuy Le , Wei Zhao , Leo Lee , Charley Mackenzie-Kludas , Neda R Mehdiabadi , Christopher Halliday , Dean Gilham , Li Fu , Stephen J. Nicholls , Jan Johansson , Michael Sweeney , Norman C.W. Wong , Ewelina Kulikowski , Kamil A. Sokolowski , Brian W. C. Tse , Lynn Devilée , Holly K Voges , Liam T Reynolds , Sophie Krumeich , Ellen Mathieson , Dad Abu-Bonsrah , Kathy Karavendzas , Brendan Griffen , Drew Titmarsh , David A Elliott , James McMahon , Andreas Suhrbier , Kanta Subbarao , Enzo R Porrello , Mark J Smyth , Christian R Engwerda , Kelli PA MacDonald , Tobias Bald , David E James , James E Hudson

Cardiac 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 1B; 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.

中文翻译:

溴结构域和末端外抑制可阻止炎症诱导的心脏功能障碍和SARS-CoV-2感染(临床前)

COVID-19患者会发生心脏损伤和功能障碍,并增加死亡风险。原因尚不明确,但可能是直接的心脏感染和/或炎症引起的功能障碍。为了确定机制和保护心脏的药物,我们使用了先进的技术流程,将人类心脏类器官与磷酸化蛋白质组学和单核RNA测序相结合。我们确定了炎性细胞因子风暴,干扰素γ,白细胞介素1B的混合物;和聚(I:C)引起的舒张功能障碍。含溴结构域的蛋白质4随病毒反应而被激活,该病毒反应在人心脏类器官和SARS-CoV-2感染的K18-hACE2小鼠心脏中均一致。溴结构域和末端外家族抑制剂(BETi)可恢复hCO的功能障碍,并在小鼠细胞因子风暴模型中完全预防心脏功能障碍和死亡。此外,BETi降低了病毒反应中基因的转录,降低了ACE2表达,并减少了心肌细胞的SARS-CoV-2感染。总之,BETi,包括FDA突破性指定的阿帕贝单独治疗药物,都是有望预防COVID-19介导的心脏损害的候选药物。
更新日期:2021-02-16
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