Haptoglobin genotype is a determinant of iron, lipid peroxidation, and macrophage accumulation in the atherosclerotic plaque
Haptoglobin genotype is a determinant of iron, lipid peroxidation, and macrophage accumulation in the atherosclerotic plaque
复制标题
DOI：
10.1161/01.atv.0000251020.24399.a2
复制
发表时间：
2007-01-01
影响因子：
8.7
通讯作者：
Moreno, Pedro R.
中科院分区：
文献类型：
--
作者：
Levy, Andrew P.;Levy, Joanne E.;Moreno, Pedro R.
目的-斑块内出血增加斑块破裂和血栓形成的风险。在出血部位从外渗的红细胞释放血红蛋白（Hb）导致铁沉积，这可能增加动脉粥样硬化斑块中的氧化和炎症。结合珠蛋白（Hp）蛋白对于保护免受Hb诱导的损伤是关键的。在Hp基因座上存在两个常见的等位基因，Hp 2等位基因与心肌梗死的风险增加相关。我们已经证明Hp 2蛋白的抗氧化和抗炎活性降低。我们测试的假设，Hp 2-2基因型与增加氧化和巨噬细胞积累在动脉粥样硬化plaic.Methods和结果-小鼠Hp基因是1型Hp等位基因。我们创建了一个小鼠2型Hp等位基因，并通过同源重组将其插入Hp基因座。C57 Bl/6 ApoE（-/-）Hp 2-2小鼠的动脉粥样硬化斑块与铁的增加有关（P = 0.008），脂质过氧化（4-羟基壬烯醛和蜡样物质）和巨噬细胞蓄积（P = 0.03）与来自C57 B1/6 ApoE（-/-）Hp 1-1小鼠的斑块相比。ApoE（-/-）Hp 2-2斑块中的脂质过氧化和巨噬细胞积聚表明Hp基因型在斑块内出血的氧化和炎症反应中起关键作用。
Objective - Intraplaque hemorrhage increases the risk of plaque rupture and thrombosis. The release of hemoglobin (Hb) from extravasated erythrocytes at the site of hemorrhage leads to iron deposition, which may increase oxidation and inflammation in the atherosclerotic plaque. The haptoglobin (Hp) protein is critical for protection against Hb-induced injury. Two common alleles exist at the Hp locus and the Hp 2 allele has been associated with increased risk of myocardial infarction. We have demonstrated decreased anti-oxidative and anti-inflammatory activity for the Hp 2 protein. We tested the hypothesis that the Hp 2-2 genotype is associated with increased oxidative and macrophage accumulation in atherosclerotic plaques.Methods and Results - The murine Hp gene is a type 1 Hp allele. We created a murine type 2 Hp allele and targeted its insertion to the Hp locus by homologous recombination. Atherosclerotic plaques from C57Bl/6 ApoE(-/-) Hp 2-2 mice were associated with increased iron (P = 0.008), lipid peroxidation (4-hydroxynonenal and ceroid) and macrophage accumulation (P = 0.03) as compared with plaques from C57Bl/6 ApoE(-/-) Hp 1-1 mice.Conclusions - Increased iron, lipid peroxidation and macrophage accumulation in ApoE(-/-) Hp 2-2 plaques suggests that the Hp genotype plays a critical role in the oxidative and inflammatory response to intraplaque hemorrhage.