Thrombosis research · 2026
Interaction between LRP1 and PAI-1 in lower extremity deep venous thrombosis.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
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Zheng Xuexun, Xue Ming, Zhou Yadong, Chen Zhongqing, Zhang Yiming, Cai Quanmin, Chen Yuhang, Guan Yunbiao
Аннотация
BACKGROUND: Lower extremity deep venous thrombosis (LEDVT) represents a critical vascular disorder with substantial clinical burden, where the mechanistic interplay between low-density lipoprotein receptor-related protein 1 (LRP1) and plasminogen activator inhibitor-1 (PAI-1) remains incompletely defined despite their implicated roles in thrombogenesis.
METHODS: This study employed integrated bioinformatic, cellular, and in vivo approaches. Protein interactions were predicted via STRING database, while co-expression patterns were analyzed using GTEx transcriptomic data. Functional validation involved: (i) ox-LDL-induced human endothelial injury models with LRP1 knockdown (shRNA lentivirus) and PAI-1 overexpression; (ii) rat LEDVT models with LRP1-targeting interventions. Molecular interactions were assessed through co-immunoprecipitation and immunofluorescence, while thrombotic phenotypes were evaluated via histopathology, ELISA, and Western blotting.
RESULTS: LRP1 and PAI-1 demonstrated significant physical interaction and co-expression in thrombotic microenvironments. LRP1 suppression markedly reduced PAI-1 expression and attenuated pro-thrombotic mediator release (endothelin-1, thromboxane B2, von Willebrand factor), while enhancing nitric oxide production. In vivo, LRP1 knockdown diminished thrombus formation severity, concurrently reducing inflammatory cytokines and restoring fibrinolytic markers. Crucially, PAI-1 restoration reversed the anti-thrombotic effects of LRP1 suppression, confirming its downstream effector role.
CONCLUSION: These findings establish LRP1 as an upstream regulator of PAI-1-driven thrombogenesis, revealing the LRP1-PAI-1 axis as a pivotal mechanistic pathway and potential therapeutic target for LEDVT.
METHODS: This study employed integrated bioinformatic, cellular, and in vivo approaches. Protein interactions were predicted via STRING database, while co-expression patterns were analyzed using GTEx transcriptomic data. Functional validation involved: (i) ox-LDL-induced human endothelial injury models with LRP1 knockdown (shRNA lentivirus) and PAI-1 overexpression; (ii) rat LEDVT models with LRP1-targeting interventions. Molecular interactions were assessed through co-immunoprecipitation and immunofluorescence, while thrombotic phenotypes were evaluated via histopathology, ELISA, and Western blotting.
RESULTS: LRP1 and PAI-1 demonstrated significant physical interaction and co-expression in thrombotic microenvironments. LRP1 suppression markedly reduced PAI-1 expression and attenuated pro-thrombotic mediator release (endothelin-1, thromboxane B2, von Willebrand factor), while enhancing nitric oxide production. In vivo, LRP1 knockdown diminished thrombus formation severity, concurrently reducing inflammatory cytokines and restoring fibrinolytic markers. Crucially, PAI-1 restoration reversed the anti-thrombotic effects of LRP1 suppression, confirming its downstream effector role.
CONCLUSION: These findings establish LRP1 as an upstream regulator of PAI-1-driven thrombogenesis, revealing the LRP1-PAI-1 axis as a pivotal mechanistic pathway and potential therapeutic target for LEDVT.