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Inhibition of IP3 (Inositol 1,4,5-Trisphosphate) Receptors Retards SARS-CoV-2-Induced Endothelial von Willebrand

Xin-Yi Yu1, Xin-Yu Jia1, Ting-Yu Wang1

  • 1The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.

Thrombosis and Haemostasis
|March 6, 2025
PubMed

Insights

Cytoskeleton-associated protein 4 (CKAP4) mediates COVID-19 coagulopathy by triggering calcium release from the endoplasmic reticulum, leading to increased von Willebrand factor secretion and thrombosis. Targeting IP3 receptors may prevent these effects.

Area of Science:

  • Biomedical research
  • Molecular biology
  • Pathophysiology

Background:

  • COVID-19 patients exhibit hypercoagulability and thrombosis.
  • Cytoskeleton-associated protein 4 (CKAP4) is a receptor for SARS-CoV-2 spike protein and linked to COVID-19 coagulopathy.
  • The precise mechanism of CKAP4-mediated thrombosis remains unclear.

Purpose of the Study:

  • To investigate the signaling pathways linking spike protein-CKAP4 interaction to von Willebrand factor (vWF) secretion and thrombosis.
  • To identify potential therapeutic targets for COVID-19-associated coagulopathy.

Main Methods:

  • Treatment of endothelial cells (ECs) with SARS-CoV-2 spike protein.
  • Use of calcium chelators (BAPTA-AM), calcium channel blockers, and inositol 1,4,5-trisphosphate (IP3) receptor inhibitors.
  • Knockdown of IP3 receptor 1 (IP3R1).
  • Administration of KT-362, an IP3R-targeting drug.
  • In vivo studies in mice with endothelial-specific CKAP4 overexpression.

Main Results:

  • Spike protein induced vWF secretion, FVIII-vWF binding, and platelet adhesion in ECs, effects blocked by BAPTA-AM.
  • Calcium release from the endoplasmic reticulum (ER) via IP3 receptors (IP3Rs) was critical for these responses.
  • Inhibition of IP3Rs, particularly IP3R1, reversed spike protein-induced vWF secretion and procoagulant state.
  • KT-362 repressed spike protein-induced vWF secretion in vitro and in vivo.
  • IP3Rs activation promoted vWF secretion independently of CKAP4.

Conclusions:

  • IP3Rs-mediated calcium release from the ER is a key mechanism in spike protein-induced vWF secretion and thrombosis.
  • Targeting IP3Rs represents a potential therapeutic strategy for managing COVID-19-associated coagulopathy.

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