Emory University Hospital Midtown, 550 Peachtree St NE, Atlanta, GA 30308, USA.
Arterioscler Thromb Vasc Biol. 2012 Feb;32(2):299-307. doi: 10.1161/ATVBAHA.111.240101. Epub 2011 Nov 17.
We recently reported that lowering of macrophage free intracellular iron increases expression of cholesterol efflux transporters ABCA1 and ABCG1 by reducing generation of reactive oxygen species. In this study, we explored whether reducing macrophage intracellular iron levels via pharmacological suppression of hepcidin can increase macrophage-specific expression of cholesterol efflux transporters and reduce atherosclerosis.
To suppress hepcidin, increase expression of the iron exporter ferroportin, and reduce macrophage intracellular iron, we used a small molecule inhibitor of bone morphogenetic protein (BMP) signaling, LDN 193189 (LDN). LDN (10 mg/kg IP b.i.d.) was administered to mice, and its effects on atherosclerosis, intracellular iron, oxidative stress, lipid efflux, and foam cell formation were measured in plaques and peritoneal macrophages. Long-term LDN administration to apolipoprotein E-/- mice increased ABCA1 immunoreactivity within intraplaque macrophages by 3.7-fold (n=8; P=0.03), reduced Oil Red O-positive lipid area by 50% (n=8; P=0.02), and decreased total plaque area by 43% (n=8; P=0.001). LDN suppressed liver hepcidin transcription and increased macrophage ferroportin, lowering intracellular iron and hydrogen peroxide production. LDN treatment increased macrophage ABCA1 and ABCG1 expression, significantly raised cholesterol efflux to ApoA-1, and decreased foam cell formation. All preceding LDN-induced effects on cholesterol efflux were reversed by exogenous hepcidin administration, suggesting modulation of intracellular iron levels within macrophages as the mechanism by which LDN triggers these effects.
These data suggest that pharmacological manipulation of iron homeostasis may be a promising target to increase macrophage reverse cholesterol transport and limit atherosclerosis.
我们最近报道称，通过降低巨噬细胞游离细胞内铁水平，减少活性氧的产生，可增加胆固醇外流转运蛋白 ABCA1 和 ABCG1 的表达。在本研究中，我们探讨了通过抑制铁调素来降低巨噬细胞内铁水平是否可以增加巨噬细胞特异性胆固醇外流转运蛋白的表达并减少动脉粥样硬化。
为了抑制铁调素、增加铁输出蛋白 ferroportin 的表达并降低巨噬细胞内铁水平，我们使用了一种骨形态发生蛋白（BMP）信号的小分子抑制剂 LDN 193189（LDN）。给予 LDN（10mg/kg，IP，bid），并在斑块和腹腔巨噬细胞中测量其对动脉粥样硬化、细胞内铁、氧化应激、脂质外流和泡沫细胞形成的影响。长期给予载脂蛋白 E-/- 小鼠 LDN 可使斑块内巨噬细胞内 ABCA1 免疫反应性增加 3.7 倍（n=8；P=0.03），使油红 O 阳性脂质面积减少 50%（n=8；P=0.02），并使总斑块面积减少 43%（n=8；P=0.001）。LDN 抑制肝铁调素转录并增加巨噬细胞 ferroportin，降低细胞内铁和过氧化氢的产生。LDN 治疗可增加巨噬细胞 ABCA1 和 ABCG1 的表达，显著提高载脂蛋白 A-1 的胆固醇外流，并减少泡沫细胞的形成。LDN 诱导的所有上述胆固醇外流作用均被外源性铁调素给药逆转，表明调节巨噬细胞内铁水平是 LDN 引发这些作用的机制。
这些数据表明，铁稳态的药理学调节可能是增加巨噬细胞逆向胆固醇转运和限制动脉粥样硬化的有希望的靶点。
