From the Cardiovascular Research Center and Cardiology Division of the Department of Medicine (R.M., H.J.B., M.D.B., C.L.S., H.S., D.K.R., K.D.B.), Massachusetts General Hospital and Harvard Medical School, Boston.
the Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine (F.W., A.B., C.D.O., C.D.L., K.M.P., B.C., K.B.J., K.D.B., D.B.B.), Massachusetts General Hospital and Harvard Medical School, Boston.
Arterioscler Thromb Vasc Biol. 2019 Feb;39(2):178-187. doi: 10.1161/ATVBAHA.118.312215.
Objective- Inflammatory stimuli enhance the progression of atherosclerotic disease. Inflammation also increases the expression of hepcidin, a hormonal regulator of iron homeostasis, which decreases intestinal iron absorption, reduces serum iron levels and traps iron within macrophages. The role of macrophage iron in the development of atherosclerosis remains incompletely understood. The objective of this study was to investigate the effects of hepcidin deficiency and decreased macrophage iron on the development of atherosclerosis. Approach and Results- Hepcidin- and LDL (low-density lipoprotein) receptor-deficient ( Hamp/ Ldlr) mice and Hamp/ Ldlr control mice were fed a high-fat diet for 21 weeks. Compared with control mice, Hamp/ Ldlr mice had decreased aortic macrophage activity and atherosclerosis. Because hepcidin deficiency is associated with both increased serum iron and decreased macrophage iron, the possibility that increased serum iron was responsible for decreased atherosclerosis in Hamp/ Ldlr mice was considered. Hamp/ Ldlr mice were treated with iron dextran so as to produce a 2-fold increase in serum iron. Increased serum iron did not decrease atherosclerosis in Hamp/ Ldlr mice. Aortic macrophages from Hamp/ Ldlr mice had less labile free iron and exhibited a reduced proinflammatory (M1) phenotype compared with macrophages from Hamp/ Ldlr mice. THP1 human macrophages treated with an iron chelator were used to model hepcidin deficiency in vitro. Treatment with an iron chelator reduced LPS (lipopolysaccharide)-induced M1 phenotypic expression and decreased uptake of oxidized LDL. Conclusions- In summary, in a hyperlipidemic mouse model, hepcidin deficiency was associated with decreased macrophage iron, a reduced aortic macrophage inflammatory phenotype and protection from atherosclerosis. The results indicate that decreasing hepcidin activity, with the resulting decrease in macrophage iron, may prove to be a novel strategy for the treatment of atherosclerosis.
目的-炎症刺激可促进动脉粥样硬化疾病的进展。炎症还会增加铁稳态激素调节因子铁调素的表达，从而减少肠道铁吸收，降低血清铁水平，并使铁滞留在巨噬细胞内。巨噬细胞铁在动脉粥样硬化发展中的作用尚不完全清楚。本研究旨在探讨铁调素缺乏和巨噬细胞铁减少对动脉粥样硬化形成的影响。
方法和结果-铁调素缺失和 LDL 受体缺失（Hamp/Ldlr）小鼠和 Hamp/Ldlr 对照组小鼠喂食高脂肪饮食 21 周。与对照组小鼠相比，Hamp/Ldlr 小鼠的主动脉巨噬细胞活性和动脉粥样硬化程度降低。由于铁调素缺乏与血清铁增加和巨噬细胞铁减少有关，因此考虑血清铁增加是否是 Hamp/Ldlr 小鼠动脉粥样硬化减少的原因。用右旋糖酐铁处理 Hamp/Ldlr 小鼠，使血清铁增加 2 倍。增加血清铁并没有降低 Hamp/Ldlr 小鼠的动脉粥样硬化程度。与 Hamp/Ldlr 小鼠的巨噬细胞相比，Hamp/Ldlr 小鼠的主动脉巨噬细胞的不稳定游离铁较少，且表现出较少的促炎（M1）表型。用铁螯合剂处理 THP1 人巨噬细胞，模拟体外铁调素缺乏。用铁螯合剂处理可降低 LPS（脂多糖）诱导的 M1 表型表达，并减少氧化型 LDL 的摄取。
结论-总之，在高脂血症小鼠模型中，铁调素缺乏与巨噬细胞铁减少、主动脉巨噬细胞炎症表型减少和动脉粥样硬化保护有关。结果表明，降低铁调素活性，导致巨噬细胞铁减少，可能成为治疗动脉粥样硬化的一种新策略。
