SARS-CoV-2 spike protein receptor-binding domain perturbates intracellular calcium homeostasis and impairs pulmonary vascular endothelial cells

Yang, Kai1; Liu, Shiyun1; Yan, Han1,2; Lu, Wenju1; Shan, Xiaoqian1,3; Chen, Haixia1,4; Bao, Changlei1; Feng, Huazhuo1; Liao, Jing5; Liang, Shuxin1; Xu, Lei3; Tang, Haiyang1; Yuan, Jason X. -J.6; Zhong, Nanshan1,2; Wang, Jian1,2,6

2023-07-14

10.1038/s41392-023-01556-8

SIGNAL TRANSDUCTION AND TARGETED THERAPY   影响因子和分区

2095-9907

2059-3635

Exposure to the spike protein or receptor-binding domain (S-RBD) of SARS-CoV-2 significantly influences endothelial cells and induces pulmonary vascular endotheliopathy. In this study, angiotensin-converting enzyme 2 humanized inbred (hACE2 Tg) mice and cultured pulmonary vascular endothelial cells were used to investigate how spike protein/S-RBD impacts pulmonary vascular endothelium. Results show that S-RBD leads to acute-to-prolonged induction of the intracellular free calcium concentration ([Ca2+](i)) via acute activation of TRPV4, and prolonged upregulation of mechanosensitive channel Piezo1 and store-operated calcium channel (SOCC) key component Orai1 in cultured human pulmonary arterial endothelial cells (PAECs). In mechanism, S-RBD interacts with ACE2 to induce formation of clusters involving Orai1, Piezo1 and TRPC1, facilitate the channel activation of Piezo1 and SOCC, and lead to elevated apoptosis. These effects are blocked by Kobophenol A, which inhibits the binding between S-RBD and ACE2, or intracellular calcium chelator, BAPTA-AM. Blockade of Piezo1 and SOCC by GsMTx4 effectively protects the S-RBD-induced pulmonary microvascular endothelial damage in hACE2 Tg mice via normalizing the elevated [Ca2+](i). Comparing to prototypic strain, Omicron variants (BA.5.2 and XBB) of S-RBD induces significantly less severe cell apoptosis. Transcriptomic analysis indicates that prototypic S-RBD confers more severe acute impacts than Delta or Lambda S-RBD. In summary, this study provides compelling evidence that S-RBD could induce persistent pulmonary vascular endothelial damage by binding to ACE2 and triggering [Ca2+](i) through upregulation of Piezo1 and Orai1. Targeted inhibition of ACE2-Piezo1/SOCC-[Ca2+](i) axis proves a powerful strategy to treat S-RBD-induced pulmonary vascular diseases.

SCI

英语

其他

National Key Research and Development Program["2022YFE0131500","2018YFC1311900"] ; National Natural Science Foundation of China["81970057","82120108001","82170065","82241012"] ; Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program[2017BT01S155] ; Guangzhou Basic Research Program Municipal School (Hospital) Joint Funded Foundation and Application Basic Research Project[ZNSA-2020003] ; Guangdong Basic and Applied Basic Research Foundation[2021A1515010767] ; Open Research Funds from The Sixth Affiliated Hospital of Guangzhou Medical University (Qingyuan People's Hospital)["202201-101","202201-309"] ; Independent Project of State Key Laboratory of Respiratory Disease[SKLRD-Z-202219]

Biochemistry & Molecular Biology ; Cell Biology

Biochemistry & Molecular Biology ; Cell Biology

WOS:001028769200001

SPRINGERNATURE

2-s2.0-85164756197

Web of Science

1.Guangzhou Med Univ, Affiliated Hosp 1, Guangzhou, Guangdong, Peoples R China
2.Guangzhou Natl Lab, Guangzhou Int Bio Isl, Guangzhou, Guangdong, Peoples R China
3.Inner Mongolia Med Univ, Affiliated Hosp, Dept Pulm & Crit Care Med, Hohhot, Peoples R China
4.Guangzhou Med Univ, Affiliated Canc Hosp, Dept Pathol, Guangzhou, Guangdong, Peoples R China
5.Southern Univ Sci & Technol, Sch Med, Shenzhen, Guangdong, Peoples R China
6.Univ Calif San Diego, Dept Med, Div Pulm Crit Care & Sleep Med, Sect Physiol, La Jolla, CA 92093 USA

Yang, Kai,Liu, Shiyun,Yan, Han,et al. SARS-CoV-2 spike protein receptor-binding domain perturbates intracellular calcium homeostasis and impairs pulmonary vascular endothelial cells[J]. SIGNAL TRANSDUCTION AND TARGETED THERAPY,2023,8(1).

Yang, Kai.,Liu, Shiyun.,Yan, Han.,Lu, Wenju.,Shan, Xiaoqian.,...&Wang, Jian.(2023).SARS-CoV-2 spike protein receptor-binding domain perturbates intracellular calcium homeostasis and impairs pulmonary vascular endothelial cells.SIGNAL TRANSDUCTION AND TARGETED THERAPY,8(1).

Yang, Kai,et al."SARS-CoV-2 spike protein receptor-binding domain perturbates intracellular calcium homeostasis and impairs pulmonary vascular endothelial cells".SIGNAL TRANSDUCTION AND TARGETED THERAPY 8.1(2023).