Red cells, hemoglobin, heme, iron, and atherogenesis.
Red cells, hemoglobin, heme, iron, and atherogenesis.
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DOI：
10.1161/atvbaha.110.206433
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发表时间：
2010-07
期刊：
影响因子：
--
通讯作者：
Balla J
中科院分区：
文献类型：
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作者：
Nagy E;Eaton JW;Jeney V;Soares MP;Varga Z;Galajda Z;Szentmiklósi J;Méhes G;Csonka T;Smith A;Vercellotti GM;Balla G;Balla J
我们研究了动脉粥样硬化病变的红细胞浸润是否会促进动脉粥样硬化的后期阶段。我们发现，在破裂的晚期病变中，铁 (FeII) 血红蛋白发生氧化，生成铁 (FeIII) 血红蛋白，并通过更广泛的氧化铁 (FeIII/FeIV=O)。蛋白质氧化标记物二酪氨酸在复杂的病变中积累，并伴随着交联血红蛋白的形成，交联血红蛋白是铁血红蛋白的标志。正常红细胞接触来自动脉粥样硬化病变的脂质会导致溶血和释放的血红蛋白氧化。在血红蛋白和动脉粥样化脂质之间的相互作用中，血红蛋白和血红素促进进一步的脂质氧化和随后的内皮反应，例如血红素加氧酶-1的上调和对内皮的细胞毒性。血红素的氧化断裂导致铁的释放和铁驱动的斑块脂质氧化的前馈过程。触珠蛋白对血红素从球蛋白释放的抑制以及血红素结合蛋白对血红素的隔离抑制了血红蛋白介导的动脉粥样硬化病变脂质的氧化，并减弱了内皮细胞毒性。晚期动脉粥样硬化病变的内部是一个促氧化环境，其中红细胞裂解，血红蛋白被氧化为铁血红蛋白和铁血红蛋白，释放的血红素和铁促进脂质进一步氧化。这些事件放大了斑块成分的内皮细胞细胞毒性。
We have investigated whether red cell infiltration of atheromatous lesions promotes the later stages of atherosclerosis. We find that oxidation of ferro (FeII) hemoglobin in ruptured advanced lesions occurs generating ferri (FeIII) hemoglobin and via more extensive oxidation ferrylhemoglobin (FeIII/FeIV=O). The protein oxidation marker, dityrosine, accumulates in complicated lesions accompanied by the formation of crosslinked hemoglobin, a hallmark of ferrylhemoglobin. Exposure of normal red cells to lipids derived from atheromatous lesions causes hemolysis and oxidation of liberated hemoglobin. In the interactions between hemoglobin and atheroma lipids, hemoglobin and heme promote further lipid oxidation and subsequently endothelial reactions such as upregulation of heme oxygenase-1 and cytotoxicity to endothelium. Oxidative scission of heme leads to release of iron and a feed-forward process of iron-driven plaque lipid oxidation. The inhibition of heme release from globin by haptoglobin and sequestration of heme by hemopexin suppress hemoglobin-mediated oxidation of lipids of atheromatous lesions and attenuate endothelial cytotoxicity. The interior of advanced atheromatous lesions is a pro-oxidant environment in which erythrocytes lyse, hemoglobin is oxidized to ferri- and ferrylhemoglobin, and released heme and iron promote further oxidation of lipids. These events amplify the endothelial cell cytotoxicity of plaque components.