tetano
Editor, Senior Moderator
Thromb Haemost
. 2025 Mar 6.
doi: 10.1055/a-2471-8767. Online ahead of print. Inhibition of IP3 (Inositol 1,4,5-Trisphosphate) Receptors Retards SARS-CoV-2-Induced Endothelial von Willebrand Factor Secretion and Thrombosis
Xin-Yi Yu[SUP] 1 [/SUP], Xin-Yu Jia[SUP] 1 [/SUP], Ting-Yu Wang[SUP] 1 [/SUP], Yan-Hong Zhang[SUP] 1 [/SUP], Hao Song[SUP] 1 [/SUP], Kan Li[SUP] 1 [/SUP], Zhuo-Zheng Chen[SUP] 1 [/SUP], Yi Zhu[SUP] 1 [/SUP], Liu Yao[SUP] 1 [/SUP]
Affiliations
Patients with coronavirus disease 2019 (COVID-19) are at high risk of developing a hypercoagulable state and thrombosis. The von Willebrand factor (vWF) produced by endothelial cells (ECs) is a critical thrombosis regulator. We previously found that cytoskeleton-associated protein 4 (CKAP4) is a novel receptor for the spike protein of severe acute respiratory syndrome coronavirus-2 and is involved in COVID-19-associated coagulopathy. However, the underlying mechanism involved remains unclear. This study aimed to explore the signaling pathways involved in spike protein-CKAP4-induced vWF secretion and thrombosis. Treatment of ECs with the spike protein significantly induced vWF secretion, coagulation factor VIII (FVIII)-vWF binding, and platelet adhesion to ECs, which were blocked by the selective intracellular calcium chelator, BAPTA-AM. Furthermore, using several calcium channel-blocking drugs and small-molecule inhibitors, we found that calcium released from the endoplasmic reticulum (ER) is involved in this process. IP3 (inositol 1,4,5-trisphosphate) receptors (IP3Rs) inhibition ameliorated spike protein-induced vWF secretion, FVIII-vWF binding affinity, and platelet adhesion to ECs. Specifically, the knockdown of IP3R1, a crucial type of IP3Rs, reversed spike protein-induced endothelial vWF secretion, and the procoagulant state. Moreover, KT-362, an investigational and clinically relevant antihypertensive drug targeting IP3Rs-mediated calcium release, repressed spike protein-induced endothelial vWF secretion. Conversely, the IP3Rs agonist promoted endothelial vWF secretion, which was not affected by CKAP4 knockdown. In vivo treatment of endothelial-specific human CKAP4 overexpression mice with KT-362 retarded spike protein-induced vWF secretion and thrombosis. Thus, IP3Rs mediated calcium release from the ER and contributed to spike protein-induced vWF secretion and thrombosis, making them potential therapeutic targets for COVID-19-associated coagulopathy.
. 2025 Mar 6.
doi: 10.1055/a-2471-8767. Online ahead of print. Inhibition of IP3 (Inositol 1,4,5-Trisphosphate) Receptors Retards SARS-CoV-2-Induced Endothelial von Willebrand Factor Secretion and Thrombosis
Xin-Yi Yu[SUP] 1 [/SUP], Xin-Yu Jia[SUP] 1 [/SUP], Ting-Yu Wang[SUP] 1 [/SUP], Yan-Hong Zhang[SUP] 1 [/SUP], Hao Song[SUP] 1 [/SUP], Kan Li[SUP] 1 [/SUP], Zhuo-Zheng Chen[SUP] 1 [/SUP], Yi Zhu[SUP] 1 [/SUP], Liu Yao[SUP] 1 [/SUP]
Affiliations
- PMID: 40049586
- DOI: 10.1055/a-2471-8767
Patients with coronavirus disease 2019 (COVID-19) are at high risk of developing a hypercoagulable state and thrombosis. The von Willebrand factor (vWF) produced by endothelial cells (ECs) is a critical thrombosis regulator. We previously found that cytoskeleton-associated protein 4 (CKAP4) is a novel receptor for the spike protein of severe acute respiratory syndrome coronavirus-2 and is involved in COVID-19-associated coagulopathy. However, the underlying mechanism involved remains unclear. This study aimed to explore the signaling pathways involved in spike protein-CKAP4-induced vWF secretion and thrombosis. Treatment of ECs with the spike protein significantly induced vWF secretion, coagulation factor VIII (FVIII)-vWF binding, and platelet adhesion to ECs, which were blocked by the selective intracellular calcium chelator, BAPTA-AM. Furthermore, using several calcium channel-blocking drugs and small-molecule inhibitors, we found that calcium released from the endoplasmic reticulum (ER) is involved in this process. IP3 (inositol 1,4,5-trisphosphate) receptors (IP3Rs) inhibition ameliorated spike protein-induced vWF secretion, FVIII-vWF binding affinity, and platelet adhesion to ECs. Specifically, the knockdown of IP3R1, a crucial type of IP3Rs, reversed spike protein-induced endothelial vWF secretion, and the procoagulant state. Moreover, KT-362, an investigational and clinically relevant antihypertensive drug targeting IP3Rs-mediated calcium release, repressed spike protein-induced endothelial vWF secretion. Conversely, the IP3Rs agonist promoted endothelial vWF secretion, which was not affected by CKAP4 knockdown. In vivo treatment of endothelial-specific human CKAP4 overexpression mice with KT-362 retarded spike protein-induced vWF secretion and thrombosis. Thus, IP3Rs mediated calcium release from the ER and contributed to spike protein-induced vWF secretion and thrombosis, making them potential therapeutic targets for COVID-19-associated coagulopathy.