Heme oxygenase-1 inhibits atherosclerotic lesion formation in LDL-receptor knockout mice
Heme oxygenase-1 inhibits atherosclerotic lesion formation in LDL-receptor knockout mice
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DOI：
10.1161/01.res.88.5.506
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发表时间：
2001-03-16
影响因子：
20.1
通讯作者：
Lusis, AJ
中科院分区：
文献类型：
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作者：
Ishikawa, K;Sugawara, D;Lusis, AJ
血红素加氧酶-1 （HO-1）是由多种与氧化应激相关的条件诱导的。我们证明了轻度氧化的LDL在人主动脉内皮细胞和平滑肌细胞共培养中显著诱导HO-1，并且其诱导导致体外轻度氧化LDL处理引起的单核细胞趋化性的衰减。为了阐明HO-1在体内动脉粥样硬化病变发展中的作用，我们在喂食高脂肪饮食的低密度脂蛋白受体敲除小鼠中调节HO-1的表达。在为期6周的高脂饮食试验中，腹腔注射血红素（H组）或血红素加去铁胺（HD组）诱导HO-1， Sn-原卟啉IX抑制HO-1 （Sn组），生理盐水作为对照（C组）。与C组相比，H组和HD组近端动脉粥样硬化平均病变明显减少，而Sn组近端动脉粥样硬化平均病变明显增大。通过Northern blot分析和HO活性测定证实了HO表达和HO活性的调节。免疫组织化学研究显示，HO-1在动脉粥样硬化病变中表达显著，氧化磷脂也局限于此。在病变中表达HO-1的主要细胞类型是巨噬细胞和泡沫细胞，HO调节影响血浆脂质过氧化氢（LPO）水平和亚硝酸盐/硝酸盐水平。这些结果表明，在高脂血症诱导下，HO-1可能通过抑制脂质过氧化和影响一氧化氮途径，作为防止动脉粥样硬化病变形成的内在保护因子。
Heme oxygenase-1 (HO-1) is induced by a variety of conditions associated with oxidative stress. We demonstrated that mildly oxidized LDL markedly induces HO-1 in human aortic endothelial and smooth muscle cell cocultures and that its induction results in the attenuation of monocyte chemotaxis resulting from treatment with mildly oxidized LDL in vitro. To elucidate the role of HO-1 in the development of atherosclerotic lesions in vivo, we modulated HO-1 expression in LDL-receptor knockout mice fed high-fat diets. During 6-week high-fat diet trials, intraperitoneal injections of hemin (H group) or hemin and desferrioxamine (HD group) to induce HO-1, Sn-protoporphyrin IX to inhibit HO-1 (Sn group), and saline as control (C group) were performed. Both the H and HD groups showed significantly less mean atherosclerotic lesions in the proximal aorta compared with the C group, whereas the Sn group showed larger lesion compared with the C group. Modulation of HO expression and HO activities were confirmed by Northern blot analysis and HO activity assay. Immunohistochemical studies revealed significant HO-1 expression in atherosclerotic lesions, where oxidized phospholipids also localized. Major cell types expressing HO-1 were macrophages and foam cells in the lesions, HO modulations affected plasma lipid hydroperoxide (LPO) levels and nitrite/nitrate levels. These results suggest that HO-1, induced under hyperlipidemia, functioned as an intrinsic protective factor against atherosclerotic lesion formation, possibly by inhibiting lipid peroxidation and influencing the nitric oxide pathway.