Balla József, Vercellotti Gregory M, Jeney Viktória, Yachie Akihiro, Varga Zsuzsa, Eaton John W, Balla György
Department of Medicine, University of Debrecen, Debrecen, Hungary.
Mol Nutr Food Res. 2005 Nov;49(11):1030-43. doi: 10.1002/mnfr.200500076.
Iron-derived reactive oxygen species are implicated in the pathogenesis of numerous vascular disorders including atherosclerosis, microangiopathic hemolytic anemia, vasculitis, and reperfusion injury. One abundant source of redox active iron is heme, which is inherently dangerous when released from intracellular heme proteins. The present review concerns the involvement of heme in vascular endothelial cell damage and the strategies used by endothelium to minimize such damage. Exposure of endothelium to heme greatly potentiates cell killing mediated by polymorphonuclear leukocytes and other sources of reactive oxygen. Free heme also promotes the conversion of low-density lipoprotein (LDL) into cytotoxic oxidized products. Only because of its abundance, hemoglobin probably represents the most important potential source of heme within the vascular endothelium; hemoglobin in plasma, when oxidized, transfers heme to endothelium and LDL, thereby enhancing cellular susceptibility to oxidant-mediated injury. As a defense against such toxicity, upon exposure to heme or hemoglobin, endothelial cells up-regulate heme oxygenase-1 and ferritin. Heme oxygenase-1 is a heme-degrading enzyme that opens the porphyrin ring, producing biliverdin, carbon monoxide, and the most dangerous product - free redox active iron. The latter can be effectively controlled by ferritin via sequestration and ferroxidase activity. Ferritin serves as a protective gene by virtue of antioxidant, antiapoptotic, and antiproliferative actions. These homeostatic adjustments have been shown effective in the protection of endothelium against the damaging effects of exogenous heme and oxidants. The central importance of this protective system was recently highlighted by a child diagnosed with heme oxygenase-1 deficiency, who exhibited extensive endothelial damage.
铁衍生的活性氧与多种血管疾病的发病机制有关，包括动脉粥样硬化、微血管病性溶血性贫血、血管炎和再灌注损伤。氧化还原活性铁的一个丰富来源是血红素，当它从细胞内血红素蛋白中释放出来时具有内在危险性。本综述关注血红素在血管内皮细胞损伤中的作用以及内皮细胞用于最小化此类损伤的策略。内皮细胞暴露于血红素会极大地增强由多形核白细胞和其他活性氧来源介导的细胞杀伤作用。游离血红素还会促进低密度脂蛋白（LDL）转化为细胞毒性氧化产物。仅因其含量丰富，血红蛋白可能是血管内皮中血红素最重要的潜在来源；血浆中的血红蛋白被氧化后，会将血红素转移到内皮细胞和低密度脂蛋白上，从而增强细胞对氧化介导损伤的易感性。作为对这种毒性的防御，内皮细胞在暴露于血红素或血红蛋白时会上调血红素加氧酶-1和铁蛋白。血红素加氧酶-1是一种降解血红素的酶，它打开卟啉环，产生胆绿素、一氧化碳以及最危险的产物——游离的氧化还原活性铁。后者可通过铁蛋白的螯合和铁氧化酶活性得到有效控制。铁蛋白凭借抗氧化、抗凋亡和抗增殖作用而成为一种保护基因。这些稳态调节已被证明能有效保护内皮细胞免受外源性血红素和氧化剂的破坏作用。最近，一名被诊断为血红素加氧酶-1缺乏症的儿童表现出广泛的内皮损伤，这突出了这个保护系统的核心重要性。
