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<p>Pulmonary vascular remodeling (PVR) is primarily driven by the aberrant proliferation and migration of vascular cells, with pulmonary artery smooth muscle cells (PASMCs) playing a central role. High mobility group protein B1 (HMGB1), a damage-associated molecular pattern (DAMP) molecule, is released via apoptosis, necrosis, or inflammatory cell activation and contributes to the pathological progression of various cardiopulmonary diseases. However, the mechanism by which HMGB1 regulates PASMCs to participate in PVR remains to be elucidated. PASMCs were stimulated with recombinant HMGB1. Proliferation of PASMCs was detected using CCK-8 and EdU assays, and migration of PASMCs was assessed by cell scratch and Transwell experiments. RNA-Seq was performed to profile transcriptomic changes in HMGB1-treated PASMCs, followed by bioinformatic analysis to identify DEGs and associated signaling pathways. Validation of DEGs was conducted using qRT-PCR and Western blotting. Monocrotaline (MCT) constructs a rat pulmonary vascular remodeling model to verify protein expression levels. HMGB1 treatment upregulated MAP2K3 expression and activated p38 phosphorylation in PASMCs, driving cell proliferation and migration. Silencing MAP2K3 or administering the p38 inhibitor SB203580 reversed the HMGB1-induced cellular functional changes and downregulated the expression of inflammatory cytokines (IL-1β, IL-6, TNF-α). HMGB1 also upregulated the Bcl-2/Bax ratio, inducing apoptosis resistance, while the inhibitors restored apoptotic balance. In a rat model of MCT-induced pulmonary vascular remodeling, MAP2K3 expression and p38 phosphorylation levels were significantly elevated, accompanied by pathological changes such as vascular wall thickening and increased muscularization. In addition, intervention with the HMGB1 inhibitor glycyrrhizin or SB203580 blocked MAP2K3/p38 activation, alleviated pulmonary vascular remodeling, inhibited cell proliferation, and restored apoptotic balance. This study elucidates that HMGB1 may drive PASMC proliferation and migration via the MAP2K3/p38 signaling axis, thereby contributing to pulmonary vascular remodeling. These findings provide new ideas for the treatment of pulmonary vascular remodeling diseases.</p>

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HMGB1 drives pulmonary arterial smooth muscle cell proliferation and migration via the MAP2K3/p38 pathway in pulmonary vascular remodeling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月29日

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  • Ya-Mei Wang,
  • Wen-Ting Wang,
  • Jia-Yi Liang,
  • Wen-Jing Xu,
  • Hao-Yan Li,
  • Yu-Tao Gao,
  • Huan-Liang Wang

摘要

Pulmonary vascular remodeling (PVR) is primarily driven by the aberrant proliferation and migration of vascular cells, with pulmonary artery smooth muscle cells (PASMCs) playing a central role. High mobility group protein B1 (HMGB1), a damage-associated molecular pattern (DAMP) molecule, is released via apoptosis, necrosis, or inflammatory cell activation and contributes to the pathological progression of various cardiopulmonary diseases. However, the mechanism by which HMGB1 regulates PASMCs to participate in PVR remains to be elucidated. PASMCs were stimulated with recombinant HMGB1. Proliferation of PASMCs was detected using CCK-8 and EdU assays, and migration of PASMCs was assessed by cell scratch and Transwell experiments. RNA-Seq was performed to profile transcriptomic changes in HMGB1-treated PASMCs, followed by bioinformatic analysis to identify DEGs and associated signaling pathways. Validation of DEGs was conducted using qRT-PCR and Western blotting. Monocrotaline (MCT) constructs a rat pulmonary vascular remodeling model to verify protein expression levels. HMGB1 treatment upregulated MAP2K3 expression and activated p38 phosphorylation in PASMCs, driving cell proliferation and migration. Silencing MAP2K3 or administering the p38 inhibitor SB203580 reversed the HMGB1-induced cellular functional changes and downregulated the expression of inflammatory cytokines (IL-1β, IL-6, TNF-α). HMGB1 also upregulated the Bcl-2/Bax ratio, inducing apoptosis resistance, while the inhibitors restored apoptotic balance. In a rat model of MCT-induced pulmonary vascular remodeling, MAP2K3 expression and p38 phosphorylation levels were significantly elevated, accompanied by pathological changes such as vascular wall thickening and increased muscularization. In addition, intervention with the HMGB1 inhibitor glycyrrhizin or SB203580 blocked MAP2K3/p38 activation, alleviated pulmonary vascular remodeling, inhibited cell proliferation, and restored apoptotic balance. This study elucidates that HMGB1 may drive PASMC proliferation and migration via the MAP2K3/p38 signaling axis, thereby contributing to pulmonary vascular remodeling. These findings provide new ideas for the treatment of pulmonary vascular remodeling diseases.