Expression of class A scavenger receptor is enhanced by high glucose in vitro and under diabetic conditions in vivo
Expression of class A scavenger receptor is enhanced by high glucose in vitro and under diabetic conditions in vivo
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DOI：
10.1074/jbc.m408715200
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发表时间：
2005-02-04
影响因子：
4.8
通讯作者：
Horiuchi, S
中科院分区：
文献类型：
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作者：
Fukuhara-Takaki, K;Sakai, M;Horiuchi, S
在动脉粥样硬化早期，巨噬细胞通过清道夫受体摄取化学修饰的低密度脂蛋白（LDL），导致动脉粥样硬化病变形成泡沫细胞。为了深入了解清道夫受体在糖尿病增强的动脉粥样硬化并发症中的作用，本研究测定了体外高糖暴露对a类清道夫受体（SR-A）以及体内糖尿病状况的影响。体外实验表明，暴露于人单核细胞源性巨噬细胞的高葡萄糖导致SR-A表达增加，同时乙酰化LDL和氧化LDL的内吞增加。内吞过程被抗sr - a中和抗体显著抑制。稳定性分析显示，SR-A在mRNA水平上的稳定性显著增加，而在蛋白质水平上没有，这表明高糖诱导的SR-A上调主要是由于SR-A mRNA的稳定性增加。蛋白激酶C和NAD(P)H氧化酶抑制剂以及抗氧化剂可抑制高糖增强的SR-A表达。在这些细胞中可见高葡萄糖增强的细胞内过氧化物的产生，这被抗氧化剂减弱。体内实验表明，与非糖尿病小鼠相比，链脲佐菌素诱导的糖尿病小鼠腹腔巨噬细胞的SR-A表达增加。这些巨噬细胞对乙酰化LDL和氧化LDL的内吞降解也增加，而对糖尿病SR-A敲除小鼠的相应巨噬细胞则没有增加。这些体外和体内实验结果可能表明，由蛋白激酶c依赖的NAD(P)H氧化酶途径产生的活性氧在高糖诱导的SR-A上调中发挥作用，导致修饰LDL的内噬降解增加，以形成泡沫细胞。这可能是糖尿病患者动脉粥样硬化发生率增加的机制之一。
In the early stage of atherosclerosis, macrophages take up chemically modified low density lipoproteins (LDL) through the scavenger receptors, leading to foam cell formation in atherosclerotic lesions. To get insight into a role of the scavenger receptors in diabetes-enhanced atherosclerotic complications, the effects on class A scavenger receptor (SR-A) of high glucose exposure in vitro as well as the diabetic conditions in vivo were determined in the present study. The in vitro experiments demonstrated that high glucose exposure to human monocyte-derived macrophages led to an increased SR-A expression with a concomitant increase in the endocytic uptake of acetylated LDL and oxidized LDL. The endocytic process was significantly suppressed by an anti-SR-A neutralizing antibody. Stability analyses revealed a significant increased stability of SR-A at a mRNA level but not a protein level, indicating that high glucose-induced up-regulation of SR-A is due largely to increased stability of SR-A mRNA. High glucose-enhanced SR-A expression was prevented by protein kinase C and NAD(P)H oxidase inhibitors as well as antioxidants. High glucose-enhanced production of intracellular peroxides was visualized in these cells, which was attenuated by an antioxidant. The in vivo experiments demonstrated that peritoneal macrophages from streptozotocin-induced diabetic mice increased SR-A expression when compared with those from nondiabetic mice. Endocytic degradation of acetylated LDL and oxidized LDL were also increased with these macrophages but not with the corresponding macrophages from diabetic SR-A knock-out mice. These in vitro and in vivo results probably suggest that reactive oxygen species generated from a protein kinase C-dependent NAD(P)H oxidase pathway plays a role in the high glucose-induced up-regulation of SR-A, leading to the increased endocytic degradation of modified LDL for foam cell formation. This could be one mechanism for an increased rate of atherosclerosis in patients with diabetes.