2. Academic Validation
  3. Homocysteine activates endothelial TP receptor to promote von Willebrand factor secretion and thrombosis

Homocysteine activates endothelial TP receptor to promote von Willebrand factor secretion and thrombosis

  • J Mol Cell Cardiol. 2025 Nov 1:210:59-71. doi: 10.1016/j.yjmcc.2025.10.013.
Jiachen Zhang 1,  Xinyu Jia 2,  Ping Zhu 3,  Mengzheng Zhao 2,  Haodong Du 4,  Xinyi Yu 2,  Jing Huang 2,  Yegong Xie 5,  Yequn Chen 6,  Yi Zhu 2,  Qiankun Bao 7,  Jinlong He 8,  Liu Yao 9
Affiliations

Affiliations

  • 1 Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin 300052, China; NHC Key Laboratory of Hormones and Development; the Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics; Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China.
  • 2 NHC Key Laboratory of Hormones and Development; the Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics; Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China.
  • 3 Department of Physical Education, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 4 Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, the Second Hospital of Tianjin Medical University, Tianjin 300211, China.
  • 5 Department of Anesthesiology, Tianjin Medical University General Hospital. 300052, China.
  • 6 Department of Cardiology, First Affiliated Hospital of Shantou University Medical College, Guangdong 515041, China.
  • 7 Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, the Second Hospital of Tianjin Medical University, Tianjin 300211, China. Electronic address: baoqiankun@tmu.edu.cn.
  • 8 NHC Key Laboratory of Hormones and Development; the Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics; Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China. Electronic address: hejinlong@tmu.edu.cn.
  • 9 NHC Key Laboratory of Hormones and Development; the Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics; Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China. Electronic address: yaoliu@tmu.edu.cn.
PMID: 41183610 DOI: 10.1016/j.yjmcc.2025.10.013
Abstract

Hyperhomocysteinemia (HHcy), characterized by elevated plasma homocysteine (Hcy) levels, is a recognized risk factor for thrombosis and an independent contributor to acute coronary syndrome, although its underlying mechanisms are not fully understood. The current study is to investigate the impact of HHcy on arterial thrombosis and the underlying mechanisms. In this study, we established an HHcy mouse model using a high-methionine diet and found that HHcy significantly accelerated thrombosis. We identified that Hcy enhanced von Willebrand factor (vWF) secretion from endothelial cells, leading to increased FVIII-vWF binding and platelet adhesion. Moreover, we observed a significant positive correlation between vWF and Hcy levels in the plasma of 150 patients with acute coronary syndrome. Mechanistically, GPCR screening revealed that Hcy-induced increase in vWF levels was mediated by activating the thromboxane prostanoid receptor (TPr) on endothelial cells. Hcy might function as an endogenous ligand binding to TPr and subsequently activated the Gαq-PLC-Ca2+ pathway to promote vWF secretion. Pharmacological inhibition or endothelial-specific deletion of TPr effectively reduced plasma vWF levels and protected against HHcy-related thrombosis. Our findings underscored the pivotal role of TPr in mediating Hcy-induced procoagulant states and suggested that targeting the TPr signaling pathway could be a promising therapeutic strategy for treating HHcy-related thrombosis.

Keywords

Endothelial cell; Hyperhomocysteinemia; Thrombosis; Thromboxane prostanoid receptor; von Willebrand factor.

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