Hyperlipidemia in concert with hyperglycemia stimulates the proliferation of macrophages in atherosclerotic lesions - Potential role of glucose-oxidized LDL
Hyperlipidemia in concert with hyperglycemia stimulates the proliferation of macrophages in atherosclerotic lesions - Potential role of glucose-oxidized LDL
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DOI：
10.2337/diabetes.53.12.3217
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发表时间：
2004-12-01
期刊：
影响因子：
7.7
通讯作者：
Bornfeldt, KE
中科院分区：
文献类型：
--
作者：
Lamharzi, N;Renard, CB;Bornfeldt, KE
高血糖和高脂血症是糖尿病加速动脉粥样硬化的重要危险因素。巨噬细胞增殖与动脉粥样硬化的进展有关。因此，我们研究了高血糖和高脂血症对小鼠动脉粥样硬化病变和分离的原代巨噬细胞增殖的影响。高血糖低密度脂蛋白受体缺陷小鼠被喂食无胆固醇饮食12周后，与非糖尿病小鼠相比，胆固醇水平没有升高，并且没有证据表明动脉粥样硬化病变处巨噬细胞增殖增加。此外，葡萄糖水平升高并没有增加小鼠腹膜巨噬细胞的增殖。相反，高血糖低密度脂蛋白受体缺乏的小鼠被喂食富含胆固醇的饮食，显示胆固醇水平升高，同时巨噬细胞在动脉粥样硬化病变中增殖。葡萄糖促进体外LDL的脂质和蛋白质氧化。葡萄糖氧化LDL导致细胞外信号调节激酶和蛋白激酶B/Akt磷酸化，刺激离体巨噬细胞增殖。葡萄糖氧化LDL的有丝分裂作用是由CD36和蛋白激酶c依赖性和磷脂酰肌醇诱导的细胞外信号调节激酶激活介导的。3-kinase-dependent通路。因此，高血糖不足以刺激动脉粥样硬化病变或离体巨噬细胞的巨噬细胞增殖。然而，高血糖和高脂血症的结合通过可能涉及LDL的葡萄糖依赖性氧化的途径刺激巨噬细胞增殖。
Hyperglycemia and hyperlipidemia are important risk factors for diabetes-accelerated atherosclerosis. Macrophage proliferation has been implicated in the progression of atherosclerosis. We therefore investigated the effects of hyperglycemia and hyperlipidemia on macrophage proliferation in murine atherosclerotic lesions and isolated, primary macrophages. Hyperglycemic LDL receptor-deficient mice that were fed a cholesterol-free diet for 12 weeks did not have elevated cholesterol levels compared with nondiabetic mice, and there was no evidence of increased macrophage proliferation in atherosclerotic lesions. Moreover, elevated glucose levels did not increase proliferation of isolated mouse peritoneal macrophages. In contrast, hyperglycemic LDL receptor-deficient mice that were fed a cholesterol-rich diet showed increased cholesterol levels concomitant with macrophage proliferation in atherosclerotic lesions. Glucose promoted lipid and protein oxidation of LDL in vitro. Glucose-oxidized LDL resulted in phosphorylation of extracellular signal-regulated kinase and protein kinase B/Akt and stimulated proliferation of isolated macrophages. The mitogenic effect of glucose-oxidized LDL was mediated by CD36 and by extracellular signal-regulated kinase activation induced by protein kinase C-dependent and phosphatidylinositol. 3-kinase-dependent pathways. Thus, hyperglycemia is not sufficient to stimulate macrophage proliferation in lesions of atherosclerosis or in isolated macrophages. A combination of hyperglycemia and hyperlipidemia, however, stimulates macrophage proliferation by a pathway that may involve the glucose-dependent oxidation of LDL.