Activation of the urotensin-II receptor by remdesivir induces cardiomyocyte dysfunction
Abstract 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 str...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-05-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-023-04888-x |
| _version_ | 1827947992430149632 |
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| author | Akiko Ogawa Seiya Ohira Yuri Kato Tatsuya Ikuta Shota Yanagida Xinya Mi Yukina Ishii Yasunari Kanda Motohiro Nishida Asuka Inoue Fan-Yan Wei |
| author_facet | Akiko Ogawa Seiya Ohira Yuri Kato Tatsuya Ikuta Shota Yanagida Xinya Mi Yukina Ishii Yasunari Kanda Motohiro Nishida Asuka Inoue Fan-Yan Wei |
| author_sort | Akiko Ogawa |
| collection | DOAJ |
| description | Abstract 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 Gαi/o-dependent AKT/ERK axis. Functionally, remdesivir treatment induced prolonged field potential and APD90 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 UTS2R 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 UTS2R 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. |
| first_indexed | 2024-04-09T12:47:23Z |
| format | Article |
| id | doaj.art-7d621b20a6ef4184a3101d7b3319fa5f |
| institution | Directory Open Access Journal |
| issn | 2399-3642 |
| language | English |
| last_indexed | 2024-04-09T12:47:23Z |
| publishDate | 2023-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj.art-7d621b20a6ef4184a3101d7b3319fa5f2023-05-14T11:24:52ZengNature PortfolioCommunications Biology2399-36422023-05-016111310.1038/s42003-023-04888-xActivation of the urotensin-II receptor by remdesivir induces cardiomyocyte dysfunctionAkiko Ogawa0Seiya Ohira1Yuri Kato2Tatsuya Ikuta3Shota Yanagida4Xinya Mi5Yukina Ishii6Yasunari Kanda7Motohiro Nishida8Asuka Inoue9Fan-Yan Wei10Department of Modomics Biology and Medicine, Institute of Development, Aging and Cancer (IDAC), Tohoku UniversityDepartment of Modomics Biology and Medicine, Institute of Development, Aging and Cancer (IDAC), Tohoku UniversityDepartment of Physiology, Graduate School of Pharmaceutical Sciences, Kyushu UniversityLaboratory of Molecular & Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku UniversityDivision of Pharmacology, National Institute of Health SciencesDepartment of Physiology, Graduate School of Pharmaceutical Sciences, Kyushu UniversityDepartment of Physiology, Graduate School of Pharmaceutical Sciences, Kyushu UniversityDivision of Pharmacology, National Institute of Health SciencesDepartment of Physiology, Graduate School of Pharmaceutical Sciences, Kyushu UniversityLaboratory of Molecular & Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku UniversityDepartment of Modomics Biology and Medicine, Institute of Development, Aging and Cancer (IDAC), Tohoku UniversityAbstract 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 Gαi/o-dependent AKT/ERK axis. Functionally, remdesivir treatment induced prolonged field potential and APD90 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 UTS2R 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 UTS2R 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.https://doi.org/10.1038/s42003-023-04888-x |
| spellingShingle | Akiko Ogawa Seiya Ohira Yuri Kato Tatsuya Ikuta Shota Yanagida Xinya Mi Yukina Ishii Yasunari Kanda Motohiro Nishida Asuka Inoue Fan-Yan Wei Activation of the urotensin-II receptor by remdesivir induces cardiomyocyte dysfunction Communications Biology |
| title | Activation of the urotensin-II receptor by remdesivir induces cardiomyocyte dysfunction |
| title_full | Activation of the urotensin-II receptor by remdesivir induces cardiomyocyte dysfunction |
| title_fullStr | Activation of the urotensin-II receptor by remdesivir induces cardiomyocyte dysfunction |
| title_full_unstemmed | Activation of the urotensin-II receptor by remdesivir induces cardiomyocyte dysfunction |
| title_short | Activation of the urotensin-II receptor by remdesivir induces cardiomyocyte dysfunction |
| title_sort | activation of the urotensin ii receptor by remdesivir induces cardiomyocyte dysfunction |
| url | https://doi.org/10.1038/s42003-023-04888-x |
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