Table_1_Irisin Suppresses Nicotine-Mediated Atherosclerosis by Attenuating Endothelial Cell Migration, Proliferation, Cell Cycle Arrest, and Cell Senescence.XLSX

Atherosclerotic disease has become the major cause of death worldwide. Smoking, as a widespread independent risk factor, further strengthens the health burden of atherosclerosis. Irisin is a cytokine that increases after physical activity and shows an atheroprotective effect, while its specific mechanism in the process of atherosclerosis is little known. The reversal effect of irisin on intimal thickening induced by smoking-mediated atherosclerosis was identified in Apoe–/– mice through the integrin αVβ5 receptor. Endothelial cells treated with nicotine and irisin were further subjected to RNA-seq for further illustrating the potential mechanism of irisin in atherosclerosis, as well as the wound healing assays, CCK-8 assays, β-gal staining and cell cycle determination to confirm phenotypic alterations. Endothelial differential expressed gene enrichment showed focal adhesion for migration and proliferation, as well as the P53 signaling pathway for cell senescence and cell cycle control. Irisin exerts antagonistic effects on nicotine-mediated migration and proliferation via the integrin αVβ5/PI3K pathway. In addition, irisin inhibits nicotine-mediated endothelial senescence and cell cycle arrest in G0/G1 phase via P53/P21 pathway. This study further illustrates the molecular mechanism of irisin in atherosclerosis and stresses its potential as an anti-atherosclerotic therapy.

动脉粥样硬化性疾病（Atherosclerotic disease）已成为全球范围内的首要致死病因。吸烟作为一种广泛存在的独立危险因素，进一步加重了动脉粥样硬化相关的健康负荷。鸢尾素（Irisin）是一种在体力活动后表达上调的细胞因子，具有抗动脉粥样硬化的保护作用，但其在动脉粥样硬化进程中的具体作用机制仍未明确。本研究通过载脂蛋白E基因敲除（Apoe–/–）小鼠，证实鸢尾素可逆转吸烟介导的动脉粥样硬化所诱导的内膜增厚，且该效应依赖于整合素αVβ5（integrin αVβ5）受体。研究进一步对经尼古丁与鸢尾素处理的内皮细胞开展RNA测序（RNA-seq），以阐明鸢尾素抗动脉粥样硬化的潜在分子机制；同时通过划痕愈合实验、CCK-8细胞增殖检测、β-半乳糖苷酶染色及细胞周期测定，验证了内皮细胞的表型改变。内皮细胞差异表达基因富集分析显示，其富集通路涵盖调控细胞迁移与增殖的黏着斑通路，以及调控细胞衰老与细胞周期的P53信号通路。鸢尾素可通过整合素αVβ5/磷脂酰肌醇3-激酶（PI3K）信号通路，拮抗尼古丁介导的内皮细胞迁移与增殖异常。此外，鸢尾素还可通过P53/P21信号通路，抑制尼古丁诱导的内皮细胞衰老及G0/G1期细胞周期阻滞。本研究进一步阐明了鸢尾素抗动脉粥样硬化的分子机制，凸显其作为抗动脉粥样硬化治疗手段的潜在应用价值。