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<p>Focal inflammation and arterial damage driven by macrophages are key pathogenic processes in atherosclerosis. However, the mechanisms that regulate these processes remain poorly understood. In this study, we demonstrate that formyl peptide receptor 1 (FPR1) agonist, a mitochondrial N-formyl peptide, is elevated in the blood of&#xa0;patients with atherosclerosis and correlates with carotid stenosis. Macrophages expressing FPR1 were found in atherosclerotic lesions. Conditional deletion of <i>Fpr1</i> in macrophages reduced plaque formation, local inflammation, and aortic atherosclerosis in apolipoprotein E (<i>ApoE</i>)<sup>−/−</sup> mice. FPR1 activates protein kinase C (PKC) in macrophages, promoting the production of reactive oxygen species (ROS), tumor necrosis factor alpha (TNF-α) and interleukin-1beta (IL-1β), which accelerates the apoptosis of endothelial cells and smooth muscle cells. To inhibit FPR1 bioactivity, we developed an antagonist, T0080. Therapeutic administration of T0080 attenuates atherosclerotic progression in <i>ApoE</i><sup>−/−</sup> mice. Our findings highlight the pivotal role of FPR1 in macrophage-mediated atherosclerotic plaque formation and support further investigation of T0080-mediated FPR1 inhibition as a potential treatment for atherosclerosis.</p>

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Formyl peptide receptor 1 and its antagonist T0080 in atherosclerosis

  • 期刊论文

  • 发表日期：

    2025年4月9日

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  • Yu-Jing Li,
  • Xue Zhao,
  • Siting Wu,
  • Nan Yao,
  • Xueyu Zhang,
  • Yanyan Liu,
  • Xiaobing Tian,
  • Yulin Li,
  • Bin Gao,
  • S. Claiborne Johnston,
  • Fu-Dong Shi,
  • Zhiguo Li

摘要

Focal inflammation and arterial damage driven by macrophages are key pathogenic processes in atherosclerosis. However, the mechanisms that regulate these processes remain poorly understood. In this study, we demonstrate that formyl peptide receptor 1 (FPR1) agonist, a mitochondrial N-formyl peptide, is elevated in the blood of patients with atherosclerosis and correlates with carotid stenosis. Macrophages expressing FPR1 were found in atherosclerotic lesions. Conditional deletion of Fpr1 in macrophages reduced plaque formation, local inflammation, and aortic atherosclerosis in apolipoprotein E (ApoE)−/− mice. FPR1 activates protein kinase C (PKC) in macrophages, promoting the production of reactive oxygen species (ROS), tumor necrosis factor alpha (TNF-α) and interleukin-1beta (IL-1β), which accelerates the apoptosis of endothelial cells and smooth muscle cells. To inhibit FPR1 bioactivity, we developed an antagonist, T0080. Therapeutic administration of T0080 attenuates atherosclerotic progression in ApoE−/− mice. Our findings highlight the pivotal role of FPR1 in macrophage-mediated atherosclerotic plaque formation and support further investigation of T0080-mediated FPR1 inhibition as a potential treatment for atherosclerosis.