Reaven P, Merat S, Casanada F, Sutphin M, Palinski W
Department of Medicine, University of California, San Diego, LA Jolla, 92093-0682, USA.
Arterioscler Thromb Vasc Biol. 1997 Oct;17(10):2250-6. doi: 10.1161/01.atv.17.10.2250.
Investigations into the mechanisms by which diabetes accelerates atherosclerosis have been hampered by the lack of suitable animal models. We hypothesized that streptozotocin-treated LDL receptor-deficient mice would be a good model of diabetic atherosclerosis because streptozotocin causes diabetes in the parent C57BL/6 strain and because in these mice diet-induced hypercholesterolemia leads to the formation of advanced atherosclerotic lesions throughout the aorta. Diabetes was induced in 18 mice by intraperitoneal injection of streptozotocin. Low-dose insulin was given subcutaneously to prevent excessive mortality and extreme elevations in triglyceride levels. The control group was subjected to sham injections. Both groups were fed a diet containing .075% cholesterol for six months. Average blood glucose was higher in the diabetic group than in the control group (257 +/- 67 mg/dL versus 111 +/- 7 mg/dL, P < 0.05). Although plasma cholesterol was similar (966 +/- 399 versus 1002 +/- 180 mg/dL) in both groups, VLDL cholesterol was higher whereas LDL cholesterol was lower in the diabetic group. Immunocytochemical analysis demonstrated significantly more advanced glycation end-product (AGE) epitopes in the artery wall of the diabetic group, whereas staining for oxidation-specific epitopes was similar in both groups. Sera of diabetic mice also contained significantly more IgG autoantibodies that bound to several AGE epitopes than did sera from control mice. Despite the presence of hyperglycemia, diabetic dyslipidemia, and enhanced AGE formation in the diabetic mice, both groups had a similar extent of atherosclerosis (diabetic, 17.3 +/- 5.2; control, 16.5 +/- 6.6% of the aortic surface). These data suggest that, at least under conditions of marked hypercholesterolemia; hyperglycemia and enhanced AGE formation do not contribute significantly to atherogenesis in LDL-/- mice.
由于缺乏合适的动物模型，对糖尿病加速动脉粥样硬化机制的研究受到了阻碍。我们推测，经链脲佐菌素处理的低密度脂蛋白受体缺陷小鼠将是糖尿病性动脉粥样硬化的良好模型，因为链脲佐菌素可使亲代C57BL/6品系发生糖尿病，且在这些小鼠中，饮食诱导的高胆固醇血症会导致整个主动脉形成晚期动脉粥样硬化病变。通过腹腔注射链脲佐菌素诱导18只小鼠患糖尿病。皮下注射低剂量胰岛素以防止过高的死亡率和甘油三酯水平的极度升高。对照组接受假注射。两组均喂食含0.075%胆固醇的饮食六个月。糖尿病组的平均血糖高于对照组（257±67mg/dL对111±7mg/dL，P<0.05）。尽管两组的血浆胆固醇相似（966±399对1002±180mg/dL），但糖尿病组的极低密度脂蛋白胆固醇较高，而低密度脂蛋白胆固醇较低。免疫细胞化学分析显示，糖尿病组动脉壁中晚期糖基化终产物（AGE）表位明显更多，而两组氧化特异性表位的染色相似。糖尿病小鼠的血清中与几种AGE表位结合的IgG自身抗体也明显多于对照小鼠的血清。尽管糖尿病小鼠存在高血糖、糖尿病性血脂异常和AGE形成增加，但两组的动脉粥样硬化程度相似（糖尿病组为主动脉表面的17.3±5.2%；对照组为16.5±6.6%）。这些数据表明，至少在明显高胆固醇血症的情况下，高血糖和AGE形成增加对LDL-/-小鼠的动脉粥样硬化发生没有显著贡献。
