Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA.
Exp Biol Med (Maywood). 2010 May;235(5):633-41. doi: 10.1258/ebm.2009.009229.
Vascular inflammation and monocyte recruitment are initiating events in atherosclerosis that have been suggested to be caused, in part, by iron-mediated oxidative stress and shifts in the intracellular redox environment of vascular cells. Therefore, the objective of this study was to investigate whether the intracellular iron chelator, desferrioxamine (DFO), reduces inflammation and atherosclerosis in experimental mice. Treatment of C57BL/6J mice with DFO (daily intraperitoneal injection of 100 mg/kg body weight for two weeks) strongly inhibited lipopolysaccharide-induced increases of soluble cellular adhesion molecules and monocyte chemoattractant protein-1 (MCP-1) in the serum and activation of the redox-sensitive transcription factors, nuclear factor-kappaB and activator protein-1, in the aorta. Furthermore, treatment of apolipoprotein E-deficient (apoE-/-) mice with DFO (100 mg/kg, intraperitoneal, daily for 10 weeks) attenuated aortic atherosclerotic lesion development by 26% (P < 0.05). DFO treatment of apoE-/- mice also lowered serum levels of MCP-1 and gene expression of proinflammatory and macrophage markers in the aorta and heart, in parallel with increased protein expression of the transferrin receptor in the heart and liver. In contrast, DFO treatment had no effect on serum cholesterol and triglyceride levels. These data show that DFO inhibits inflammation and atherosclerosis in experimental mice, providing the proof-of-concept for an important role of iron in atherogenesis. Whether eliminating excess iron is a useful adjunct for the prevention or treatment of atherosclerosis in humans remains to be investigated.
血管炎症和单核细胞募集是动脉粥样硬化的起始事件，部分原因被认为是铁介导的氧化应激和血管细胞内氧化还原环境的变化所致。因此，本研究的目的是研究细胞内铁螯合剂去铁胺（DFO）是否能减少实验小鼠的炎症和动脉粥样硬化。用 DFO（每天腹腔注射 100mg/kg 体重，持续两周）处理 C57BL/6J 小鼠，可强烈抑制脂多糖诱导的血清可溶性细胞黏附分子和单核细胞趋化蛋白-1（MCP-1）增加，以及氧化还原敏感转录因子核因子-κB 和激活蛋白-1 在主动脉中的激活。此外，用 DFO（100mg/kg，腹腔内，每天一次，持续 10 周）处理载脂蛋白 E 缺陷（apoE-/-）小鼠，可使主动脉粥样硬化病变发展减少 26%（P<0.05）。DFO 处理 apoE-/-小鼠还降低了血清 MCP-1 水平和主动脉及心脏中促炎和巨噬细胞标志物的基因表达，同时增加了心脏和肝脏中铁蛋白受体的蛋白表达。相比之下，DFO 处理对血清胆固醇和甘油三酯水平没有影响。这些数据表明，DFO 可抑制实验小鼠的炎症和动脉粥样硬化，为铁在动脉粥样形成中的重要作用提供了概念验证。消除多余的铁是否对预防或治疗人类的动脉粥样硬化有用，仍有待研究。
