Bamm Vladimir V, Tsemakhovich Vladimir A, Shaklai Matityahu, Shaklai Nurith
Department of Human Genetics and Molecular Medicine, Sackler Institute of Molecular Medicine, Tel Aviv University, 69978 Tel-Aviv, Israel.
Biochemistry. 2004 Apr 6;43(13):3899-906. doi: 10.1021/bi0362626.
LDL oxidation plays a pivotal role in atherosclerosis. Excellular hemoglobin (Hb) is a trigger of LDL oxidation. By virtue of its ability to bind hemoglobin, haptoglobin (Hp) serves as an antioxidant. Oxidation of LDL by hemoglobin was analyzed to occur by heme displacement from methemoglobin lodged in LDL. The LDL-associated heme is disintegrated, and iron inserted this way in LDL triggers formation of lipid peroxides. The genetic polymorphism of haptoglobin was found to be a risk factor in the pathogenesis of atherosclerosis. Individuals with Hp2-2 have more vascular incidences as compared to those with Hp1-1. In the current study, oxidation of LDL by metHb was carried out at physiological pH without addition of external peroxides. Hb-derived oxidation of lipids and protein was found to be practically inhibited by Hp1-1 but only partially by Hp2-2. Heme transfer from metHb to LDL was almost completely omitted by Hp1-1 and only partially by Hp2-2. We concluded that partial heme transfer from the Hb-Hp2-2 complex to LDL is the reason for oxidation of LDL lipids as well as protein. These findings provide a molecular basis for Hp2-2 atherogenic properties.
低密度脂蛋白（LDL）氧化在动脉粥样硬化中起关键作用。细胞外血红蛋白（Hb）是LDL氧化的触发因素。凭借其结合血红蛋白的能力，触珠蛋白（Hp）起到抗氧化剂的作用。分析发现，血红蛋白对LDL的氧化是通过LDL中高铁血红蛋白的血红素置换来发生的。与LDL相关的血红素分解，以这种方式插入LDL中的铁触发脂质过氧化物的形成。发现触珠蛋白的基因多态性是动脉粥样硬化发病机制中的一个危险因素。与Hp1-1个体相比，Hp2-2个体有更多的血管疾病发生。在当前研究中，高铁血红蛋白（metHb）对LDL的氧化是在生理pH值下进行的，未添加外部过氧化物。发现脂质和蛋白质的Hb衍生氧化实际上被Hp1-1抑制，但仅被Hp2-2部分抑制。从高铁血红蛋白到LDL的血红素转移几乎完全被Hp1-1阻止，仅被Hp2-2部分阻止。我们得出结论，从Hb-Hp2-2复合物到LDL的部分血红素转移是LDL脂质和蛋白质氧化的原因。这些发现为Hp2-2的致动脉粥样硬化特性提供了分子基础。
