TRPC3-Nox2 Protein Complex Formation Increases the Risk of SARS-CoV-2 Spike Protein-Induced Cardiomyocyte Dysfunction through ACE2 Upregulation.
TRPC3-Nox2 Protein Complex Formation Increases the Risk of SARS-CoV-2 Spike Protein-Induced Cardiomyocyte Dysfunction through ACE2 Upregulation.
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DOI：
10.3390/ijms24010102
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发表时间：
2022-12-21
影响因子：
5.6
通讯作者：
Nishida, Motohiro
中科院分区：
文献类型：
--
作者：
Kato, Yuri;Nishiyama, Kazuhiro;Man Lee, Jae;Ibuki, Yuko;Imai, Yumiko;Noda, Takamasa;Kamiya, Noriho;Kusakabe, Takahiro;Kanda, Yasunari;Nishida, Motohiro
关键词：
新出现的冠状病毒（SARS-CoV-2）感染引起的心肌损伤是COVID-19严重程度和死亡率的关键决定因素之一。SARS-CoV-2进入宿主细胞是通过与其受体血管紧张素转换酶（ACE）2结合而启动的，ACE 2丰度被认为反映了对感染的易感性。在这里，我们报告，异丁司特，我们以前确定为一个有效的抑制剂的蛋白复合物之间的瞬时受体电位典型（TRPC）3和NADPH氧化酶（Nox）2，减弱SARS-CoV-2刺突糖蛋白假病毒引起的收缩和代谢功能障碍的新生大鼠心肌细胞（NRCM）。流行病学报告的严重COVID-19的风险因素，包括香烟侧流烟雾（CSS）和抗癌药物治疗，通常上调ACE 2表达水平，这些都通过抑制TRPC 3-Nox 2复合物的形成而得到抑制。NRCM暴露于SARS-CoV-2假病毒以及CSS和多柔比星（Dox）诱导ATP通过泛连接蛋白-1半通道释放，并且这种ATP释放增强假病毒进入NRCM和人iPS细胞衍生的心肌细胞（hiPS-CM）。由于假病毒进入后产生活性氧通过抑制hiPS-CM中TRPC 3-Nox 2复合物而减弱，因此我们认为由泛蛋白1介导的ATP释放触发的TRPC 3-Nox 2复合物形成通过放大ACE 2依赖的SARS-CoV-2进入而参与心肌损伤的加重。
Myocardial damage caused by the newly emerged coronavirus (SARS-CoV-2) infection is one of the key determinants of COVID-19 severity and mortality. SARS-CoV-2 entry to host cells is initiated by binding with its receptor, angiotensin-converting enzyme (ACE) 2, and the ACE2 abundance is thought to reflect the susceptibility to infection. Here, we report that ibudilast, which we previously identified as a potent inhibitor of protein complex between transient receptor potential canonical (TRPC) 3 and NADPH oxidase (Nox) 2, attenuates the SARS-CoV-2 spike glycoprotein pseudovirus-evoked contractile and metabolic dysfunctions of neonatal rat cardiomyocytes (NRCMs). Epidemiologically reported risk factors of severe COVID-19, including cigarette sidestream smoke (CSS) and anti-cancer drug treatment, commonly upregulate ACE2 expression level, and these were suppressed by inhibiting TRPC3-Nox2 complex formation. Exposure of NRCMs to SARS-CoV-2 pseudovirus, as well as CSS and doxorubicin (Dox), induces ATP release through pannexin-1 hemi-channels, and this ATP release potentiates pseudovirus entry to NRCMs and human iPS cell-derived cardiomyocytes (hiPS-CMs). As the pseudovirus entry followed by production of reactive oxygen species was attenuated by inhibiting TRPC3-Nox2 complex in hiPS-CMs, we suggest that TRPC3-Nox2 complex formation triggered by panexin1-mediated ATP release participates in exacerbation of myocardial damage by amplifying ACE2-dependent SARS-CoV-2 entry.
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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
影响因子：
37.8
作者：
Bozkurt, Biykem;Kamat, Ishan;Hotez, Peter J.
通讯作者：
Hotez, Peter J.
影响因子：
5.8
作者：
Cheema PS;Nandi D;Nag A
通讯作者：
Nag A
影响因子：
82.9
作者：
Kuba K;Imai Y;Rao S;Gao H;Guo F;Guan B;Huan Y;Yang P;Zhang Y;Deng W;Bao L;Zhang B;Liu G;Wang Z;Chappell M;Liu Y;Zheng D;Leibbrandt A;Wada T;Slutsky AS;Liu D;Qin C;Jiang C;Penninger JM
通讯作者：
Penninger JM
DOI：
10.1016/j.bbrc.2020.06.020
发表时间：
2020-08-20
影响因子：
3.1
作者：
Fujita, Ryosuke;Hino, Masato;Kusakabe, Takahiro
通讯作者：
Kusakabe, Takahiro