Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, 150001, PR China; Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin, 150001, PR China.
Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, 150001, PR China; Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin, 150001, PR China.
Free Radic Biol Med. 2023 May 20;201:76-88. doi: 10.1016/j.freeradbiomed.2023.03.006. Epub 2023 Mar 16.
Despite the known promotional effects of cigarette smoking on progression of atherosclerosis (AS), tar as the most dominant toxic component in cigarette smoking has been little studied. Understanding the potential role and mechanisms of tar in AS may be a prerequisite for future reductions in cardiovascular morbidity and mortality. Male ApoE mice were fed with high-fat diet and injected intraperitoneally with cigarette tar (40 mg/kg/day) for 16 weeks. The results showed that cigarette tar significantly promoted the formation of lipid-rich plaques with larger necrotic cores and less fibrous, and caused severe iron overload and lipid peroxidation in AS lesions. Moreover, tar significantly upregulated the expression of hepcidin and downregulated FPN and SLC7A11 of macrophages in AS plaques. Ferroptosis inhibitor (FER-1 and DFO) treatment, hepcidin-knockdown or SLC7A11-overexpression reversed above changes, thereby delaying the progression of atherosclerosis. In vitro, the use of FER-1, DFO, si-hepcidin, and ov-SLC7A11 increased cell viability and inhibited iron accumulation, lipid peroxidation and GSH depletion in tar treated macrophages. These interventions also inhibited the tar induced upregulation of hepcidin, and increased the expression of FPN, SLC7A11, and GPX4. Furthermore, NF-κB inhibitor reversed the regulatory effect of tar on hepcidin/FPN/SLC7A11 axis, and then inhibiting macrophage ferroptosis. These findings indicated that cigarette tar promotes atherosclerosis progression by inducing macrophage ferroptosis via NF-κB-activated hepcidin/FPN/SLC7A11 pathway.
尽管已知吸烟会促进动脉粥样硬化（AS）的进展，但作为香烟中最主要的有毒成分的焦油，其在吸烟中的作用却研究甚少。了解焦油在 AS 中的潜在作用和机制可能是未来降低心血管发病率和死亡率的前提。雄性 ApoE 小鼠给予高脂肪饮食，并腹膜内注射香烟焦油（40mg/kg/天）16 周。结果表明，香烟焦油显著促进富含脂质斑块的形成，其坏死核心更大，纤维更少，并导致 AS 病变中铁过载和脂质过氧化严重。此外，焦油显著上调 AS 斑块中巨噬细胞的铁调素表达，下调 FPN 和 SLC7A11 的表达。铁死亡抑制剂（FER-1 和 DFO）治疗、铁调素敲低或 SLC7A11 过表达逆转了上述变化，从而延缓了动脉粥样硬化的进展。在体外，使用 FER-1、DFO、si-hepcidin 和 ov-SLC7A11 增加了细胞活力，并抑制了焦油处理的巨噬细胞中铁积累、脂质过氧化和 GSH 耗竭。这些干预措施还抑制了焦油诱导的铁调素上调，并增加了 FPN、SLC7A11 和 GPX4 的表达。此外，NF-κB 抑制剂逆转了焦油对 hepcidin/FPN/SLC7A11 轴的调节作用，从而抑制了巨噬细胞的铁死亡。这些发现表明，香烟焦油通过 NF-κB 激活的铁调素/FPN/SLC7A11 通路诱导巨噬细胞铁死亡，从而促进动脉粥样硬化的进展。
