Kunjathoor V V, Wilson D L, LeBoeuf R C
Department of Medicine, University of Washington, Seattle, 98195, USA.
J Clin Invest. 1996 Apr 1;97(7):1767-73. doi: 10.1172/JCI118604.
Premature and extensive atheroscleroses involving renal, peripheral, and cardiovascular sites remain major complications of diabetes mellitus. Controversy exists as to the contribution of hyperglycemia versus elevated local or systemic concentrations of insulin to atherosclerosis risk. In this report, we developed the first murine model susceptible to both atherosclerosis and diabetes to determine which diabetogenic factors contribute to vascular disease. C57BL/6 and BALB/c mice were treated with multiple low-dose streptozotocin (STZ) or control citrate buffer and fed rodent chow or an atherogenic-promoting (Ath) diet for 12-20 wk. STZ treatment resulted in sustained hyperglycemia (250-420 mg/dl) and a modest reduction in plasma insulin levels for both strains regardless of diet. Citrate-treated C57BL/6 mice fed the Ath diet showed extensive oil red O-staining fatty streak aortic sinus lesions (20,537+/-2,957 micron2), the size of which did not differ for Ath-fed mice treated with STZ (16,836+/-2,136 micron2). In contrast, hyperglycemic BALB/c mice fed the Ath diet showed a 17-fold increase in atherosclerotic lesion area (7,922+/-2,096 micron2) as compared with citrate-treated mice fed the Ath diet (467+/-318 micron2). Correlations between lesion size and plasma glucose levels were significant for BALB/c (r = 0.741, P < 0.009), but not C57BL/6 (r = 0.314, P<0.3) mice. Lesion size correlated significantly with plasma cholesterol for C57BL/6 (r = 0.612, P<0.03) but not BALB/c (r = 0.630, P<0.1) mice. Immunohistochemistry showed that aortic sinus lesions from both strains contained macrophages, but smooth muscle cells were clearly present in lesions of BALB/c mice. In summary, we present the first small animal model showing accelerated atherosclerosis in response to hyperglycemia. Fatty streaks resembled those of human type II lesions in that both macrophages and smooth muscle cells were evident. In addition, our results support the concept that hyperglycemia as opposed to hyperinsulinemia contributes heavily to risk of atherosclerosis.
涉及肾脏、外周和心血管部位的过早和广泛动脉粥样硬化仍然是糖尿病的主要并发症。关于高血糖与局部或全身胰岛素浓度升高对动脉粥样硬化风险的影响存在争议。在本报告中，我们开发了首个对动脉粥样硬化和糖尿病均易感的小鼠模型，以确定哪些致糖尿病因素会导致血管疾病。将C57BL/6和BALB/c小鼠用多次低剂量链脲佐菌素（STZ）或对照柠檬酸盐缓冲液处理，并喂食啮齿动物饲料或促动脉粥样硬化（Ath）饮食12 - 20周。无论饮食如何，STZ处理均导致两种品系小鼠持续高血糖（250 - 420mg/dl）且血浆胰岛素水平适度降低。喂食Ath饮食的柠檬酸盐处理的C57BL/6小鼠显示出广泛的油红O染色的主动脉窦脂肪条纹病变（20,537±2,957平方微米），喂食Ath饮食的STZ处理小鼠的病变大小与之无差异（16,836±2,136平方微米）。相比之下，喂食Ath饮食的高血糖BALB/c小鼠的动脉粥样硬化病变面积比喂食Ath饮食的柠檬酸盐处理小鼠增加了17倍（7,922±2,096平方微米对467±318平方微米）。BALB/c小鼠（r = 0.741，P < 0.009）的病变大小与血浆葡萄糖水平之间存在显著相关性，但C57BL/6小鼠（r = 0.314，P < 0.3）则不然。C57BL/6小鼠（r = 0.612，P < 0.03）的病变大小与血浆胆固醇显著相关，但BALB/c小鼠（r = 0.630，P < 0.1）则不然。免疫组织化学显示，两种品系小鼠的主动脉窦病变均含有巨噬细胞，但BALB/c小鼠的病变中明显存在平滑肌细胞。总之，我们展示了首个显示高血糖会加速动脉粥样硬化的小型动物模型。脂肪条纹类似于人类II型病变，因为巨噬细胞和平滑肌细胞均很明显。此外，我们的结果支持这样的概念，即与高胰岛素血症相反，高血糖对动脉粥样硬化风险有很大影响。
