Genetically determined heterogeneity in hemoglobin scavenging and susceptibility to diabetic cardiovascular disease
Genetically determined heterogeneity in hemoglobin scavenging and susceptibility to diabetic cardiovascular disease
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DOI：
10.1161/01.res.0000076889.23082.f1
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发表时间：
2003-06-13
影响因子：
20.1
通讯作者：
Levy, AP
中科院分区：
文献类型：
--
作者：
Asleh, R;Marsh, S;Levy, AP
结合珠蛋白（Hp）的主要功能是结合血红蛋白（Hb）形成稳定的Hp-Hb复合物，从而防止Hb诱导的氧化性组织损伤。Hp-Hb复合物的清除可由单核细胞/巨噬细胞清道夫受体CD 163介导。我们最近发现，与Hp 1等位基因纯合子（Hp 1-1）的糖尿病个体相比，Hp 2等位基因纯合子（Hp 2-2）的糖尿病个体患心血管疾病（CVD）的风险高500%。在没有糖尿病的个体中，没有发现Hp类型的风险差异。为了了解Hp多态性与糖尿病CVD之间的关系，我们试图确定Hp类型之间的抗氧化和清除功能的差异，并确定这些功能在糖尿病中是如何改变的。在用CD 163稳定转染的细胞系和表达内源性CD 163的巨噬细胞中使用罗丹明标记和I-125-Hp评估Hp的清除功能。CD_（163）对Hp_（1-1）-Hb的清除率明显高于Hp_（2-2）-Hb。糖尿病与血清蛋白（包括Hb）的非酶糖基化增加有关。用糖基化和非糖基化血红蛋白评估Hp的抗氧化功能。我们确定了一个严重损害的能力，幽门螺杆菌，以防止氧化介导的糖化血红蛋白。我们认为糖尿病、心血管疾病和Hp基因型之间的特异性相互作用是由于在低密度脂蛋白氧化修饰为致动脉粥样硬化的氧化低密度脂蛋白之前，迅速清除内皮下空间的糖化血红蛋白-Hp复合物的紧迫性提高。
A major function of haptoglobin (Hp) is to bind hemoglobin (Hb) to form a stable Hp-Hb complex and thereby prevent Hb-induced oxidative tissue damage. Clearance of the Hp-Hb complex can be mediated by the monocyte/macrophage scavenger receptor CD163. We recently demonstrated that diabetic individuals homozygous for the Hp 2 allele (Hp 2-2) were at 500% greater risk of cardiovascular disease (CVD) compared with diabetic individuals homozygous for the Hp 1 allele (Hp 1-1). No differences in risk by Hp type were seen in individuals without diabetes. To understand the relationship between the Hp polymorphism and diabetic CVD, we sought to identify differences in antioxidant and scavenging functions between the Hp types and to determine how these functions were modified in diabetes. The scavenging function of Hp was assessed using rhodamine-tagged and I-125-Hp in cell lines stably transfected with CD163 and in macrophages expressing endogenous CD163. We found that the rate of clearance of Hp 1-1-Hb by CD163 is markedly greater than that of Hp 2-2-Hb. Diabetes is associated with an increase in the nonenzymatic glycosylation of serum proteins, including Hb. The antioxidant function of Hp was assessed with glycosylated and nonglycosylated Hb. We identified a severe impairment in the ability of Hp to prevent oxidation mediated by glycosylated Hb. We propose that the specific interaction between diabetes, CVD, and Hp genotype is the result of the heightened urgency of rapidly clearing glycosylated Hb-Hp complexes from the subendothelial space before they can oxidatively modify low-density lipoprotein to atherogenic oxidized low-density lipoprotein.