2. Academic Validation
  3. BAM15 inhibits endothelial pyroptosis via the NLRP3/ASC/caspase-1 pathway to alleviate atherosclerosis

BAM15 inhibits endothelial pyroptosis via the NLRP3/ASC/caspase-1 pathway to alleviate atherosclerosis

  • Atherosclerosis. 2025 Jul:406:119226. doi: 10.1016/j.atherosclerosis.2025.119226.
Su Zhong 1,  Hui Shen 2,  Xiaoman Dai 2,  Lianming Liao 3,  Chun Huang 4
Affiliations

Affiliations

  • 1 Department of Geriatrics, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian, China; Cadre Ward, Army 73rd Group Military Hospital, Xiamen, 36100, Fujian, China.
  • 2 Department of Geriatrics, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian, China.
  • 3 Department of Laboratory Medicine, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian, China.
  • 4 Department of Geriatrics, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian, China; People's Hospital of Changji Hui Autonomous Prefecture, Changji, 831100, Xinjiang, China. Electronic address: [email protected].
PMID: 40393254 DOI: 10.1016/j.atherosclerosis.2025.119226
Abstract

Background and aims: Atherosclerosis (AS) is a chronic inflammatory disease contributing to major cardiovascular events. This study aimed to investigate the effects of BAM15, a mitochondrial uncoupler, on regulating the NLRP3/ASC/Caspase-1 signaling pathway to suppress endothelial cell Pyroptosis and mitigate AS.

Methods: AS was induced in ApoE-/- mice through a high-fat diet (HFD), and the therapeutic effects of BAM15 (5 mg/kg/day, s. c.) were evaluated. Histological analyses, including HE staining and oil red O staining, were used to assess aortic pathology and lipid deposition. Serum inflammatory cytokines (IL-1β, IL-18) were quantified by ELISA. Mouse primary aortic endothelial cells (MAECs) were treated with oxidized low-density lipoprotein (ox-LDL) to simulate AS condition in vitro. Mitochondrial Reactive Oxygen Species (mtROS) expression and oxidized (ox)-mtDNA content were detected by Mitosox staining and ELISA, respectively. Western blot was used to assess the expression of pyroptosis-related proteins, including GSDMD-NT, NLRP3, ASC, and cleaved-caspase-1.

Results: BAM15 reduced atherosclerotic plaque formation, lipid deposition, and inflammation, and diminished mtROS expression and ox-mtDNA content in the AS mouse models. In both in vivo and in vitro experiments, BAM15 markedly inhibited the activation of the NLRP3 inflammasome, leading to reduced Pyroptosis in endothelial cells. Activation of the NLRP3/ASC/Caspase-1 signaling pathway by Nigericin partially reversed the protective effects of BAM15, underscoring the pivotal role of NLRP3 inflammasome inhibition in endothelial Pyroptosis suppression.

Conclusions: BAM15 effectively inhibits endothelial cell Pyroptosis by reducing mtROS production and ox-mtDNA release to suppress the NLRP3/ASC/Caspase-1 signaling pathway, thereby alleviating AS in both in vivo and in vitro models.

Keywords

Atherosclerosis; BAM15; N-terminal fragment of gasdermin D; NLRP3/ASC/Caspase-1; Pyroptosis.

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