Activation of the urotensin-II receptor by remdesivir induces cardiomyocyte dysfunction.
Activation of the urotensin-II receptor by remdesivir induces cardiomyocyte dysfunction.
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DOI：
10.1038/s42003-023-04888-x
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发表时间：
2023-05-12
影响因子：
5.9
通讯作者：
Wei, Fan-Yan
中科院分区：
文献类型：
--
作者：
Ogawa, Akiko;Ohira, Seiya;Kato, Yuri;Ikuta, Tatsuya;Yanagida, Shota;Mi, Xinya;Ishii, Yukina;Kanda, Yasunari;Nishida, Motohiro;Inoue, Asuka;Wei, Fan-Yan
Remdesivir是全球用于COVID-19治疗的抗病毒药物。心血管副作用与remdesivir有关;然而，潜在的分子机制仍然未知。在这里，我们进行了大规模的G蛋白偶联受体筛选与结构建模相结合，并发现remdesivir是一种选择性的，部分激动剂，通过Gαi/o依赖性AKT/ERK轴的尿紧张素-II受体（UTS 2 R）。在功能上，Remdesivir治疗诱导人诱导多能干细胞（iPS）衍生的心肌细胞中的场电位和APD 90延长，以及新生儿和成人心肌细胞中的收缩性受损，所有这些都反映了临床病理学。重要的是，通过拮抗UTS 2 R信号传导，Remdesivir介导的心脏功能障碍被有效地减弱。最后，我们描述了基因组数据库中报告的UTS 2 R基因中110个单核苷酸变体的作用，并发现了4个错义变体，它们在受体对Remdesivir的敏感性中显示出功能获得效应。总的来说，我们的研究阐明了一个以前未知的机制，潜在的remdesivir相关的心血管事件，UTS 2 R基因的遗传变异可能是remdesivir治疗期间心血管事件的潜在危险因素，这共同为将来预防此类事件的治疗机会铺平了道路。SARS-CoV-2药物remdesivir是尾加压素2受体的部分激动剂，导致体外心肌细胞活动异常。
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. The SARS-CoV-2 drug remdesivir is a partial agonist for urotensin 2 receptor, leading to aberrant cardiomyocyte activity in vitro.
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DOI：
10.7759/cureus.11132
发表时间：
2020-10-24
期刊：
Cureus
影响因子：
--
作者：
Gupta AK;Parker BM;Priyadarshi V;Parker J
通讯作者：
Parker J
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
4.4
作者：
Chien M;Anderson TK;Jockusch S;Tao C;Li X;Kumar S;Russo JJ;Kirchdoerfer RN;Ju J
通讯作者：
Ju J
影响因子：
4.6
作者：
Kitajima N;Numaga-Tomita T;Watanabe M;Kuroda T;Nishimura A;Miyano K;Yasuda S;Kuwahara K;Sato Y;Ide T;Birnbaumer L;Sumimoto H;Mori Y;Nishida M
通讯作者：
Nishida M
DOI：
10.1056/nejmoa2116846
发表时间：
2022-01-27
期刊：
The New England journal of medicine
影响因子：
--
作者：
Gottlieb RL;Vaca CE;Paredes R;Mera J;Webb BJ;Perez G;Oguchi G;Ryan P;Nielsen BU;Brown M;Hidalgo A;Sachdeva Y;Mittal S;Osiyemi O;Skarbinski J;Juneja K;Hyland RH;Osinusi A;Chen S;Camus G;Abdelghany M;Davies S;Behenna-Renton N;Duff F;Marty FM;Katz MJ;Ginde AA;Brown SM;Schiffer JT;Hill JA;GS-US-540-9012 (PINETREE) Investigators
通讯作者：
GS-US-540-9012 (PINETREE) Investigators