Activation of the urotensin-II receptor by remdesivir induces cardiomyocyte dysfunction
書誌事項
- 公開日
- 2023-05-12
- 資源種別
- journal article
- 権利情報
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- https://creativecommons.org/licenses/by/4.0
- https://creativecommons.org/licenses/by/4.0
- DOI
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- 10.1038/s42003-023-04888-x
- 公開者
- Springer Science and Business Media LLC
説明
<jats:title>Abstract</jats:title><jats:p>Remdesivir is an antiviral drug used for COVID-19 treatment worldwide. Cardiovascular side effects have been associated with remdesivir; however, the underlying molecular mechanism remains unknown. Here, we performed a large-scale G-protein-coupled receptor screening in combination with structural modeling and found that remdesivir is a selective, partial agonist for urotensin-II receptor (UTS2R) through the Gα<jats:sub>i/o</jats:sub>-dependent AKT/ERK axis. Functionally, remdesivir treatment induced prolonged field potential and APD<jats:sub>90</jats:sub> in human induced pluripotent stem cell (iPS)-derived cardiomyocytes and impaired contractility in both neonatal and adult cardiomyocytes, all of which mirror the clinical pathology. Importantly, remdesivir-mediated cardiac malfunctions were effectively attenuated by antagonizing UTS2R signaling. Finally, we characterized the effect of 110 single-nucleotide variants in <jats:italic>UTS2R</jats:italic> gene reported in genome database and found four missense variants that show gain-of-function effects in the receptor sensitivity to remdesivir. Collectively, our study illuminates a previously unknown mechanism underlying remdesivir-related cardiovascular events and that genetic variations of <jats:italic>UTS2R</jats:italic> gene can be a potential risk factor for cardiovascular events during remdesivir treatment, which collectively paves the way for a therapeutic opportunity to prevent such events in the future.</jats:p>
収録刊行物
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- Communications Biology
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Communications Biology 6 (1), 511-, 2023-05-12
Springer Science and Business Media LLC
