Natarajan R, Gerrity R G, Gu J-L, Lanting L, Thomas L, Nadler J L
Gonda Diabetes Center, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.
Diabetologia. 2002 Jan;45(1):125-33. doi: 10.1007/s125-002-8253-x.
AIMS/HYPOTHESIS: We previously showed that vascular smooth muscle cells and endothelial cells cultured under high glucose conditions produced more 12(S)-hydroxyeicosatetraenoic acid (12-HETE), the 12-lipoxygenase (12-LO) product of arachidonate metabolism, relative to normal glucose. Because the lipoxygenase (LO) pathway has been associated with oxidant stress and the pathogenesis of atherosclerosis, we now examined 12-LO activation in vivo in a pig model of diabetes-induced accelerated atherosclerosis which displays human characteristics.
The animal model was developed in pigs who were fed a normal or high fat diet and given streptozotocin injections to produce normolipemic-normoglycaemic (NLNG), normolipemic-hyperglycaemic (NLHG), hyperlipemic-normoglycaemic (HLNG) and hyperlipemic-hyperglycaemic (HLHG) pigs. Tissue samples were obtained from key arterial beds to examine 12-LO expression at 20 weeks after the pigs began their diet.
All HG pigs maintained threefold higher serum glucose concentrations. The HL groups developed atherosclerosis but diabetic HLHG pigs showed markedly accelerated atherosclerosis (twofold) relative to non-diabetic HLNG pigs. Immunostaining showed progressive increases in 12-LO in arteries in the order NLNG, NLHG, HLNG and HLHG. Leukocyte-type 12-LO protein (immuno-blotting) as well as mRNA expression (by competitive PCR) in abdominal and coronary arteries were significantly greater in HLHG pigs than in all the other three groups. Furthermore, increased oxidant stress was observed in monocytes from NLHG and HLNG pigs, and greatly potentiated in HLHG pigs.
CONCLUSIONS/INTERPRETATION: These results are consistent with the hypothesis that 12-LO activation plays a key role in accelerated atherosclerosis due to diabetes and hyperlipemia.
目的/假设：我们之前发现，与在正常葡萄糖条件下培养的血管平滑肌细胞和内皮细胞相比，在高葡萄糖条件下培养的这些细胞会产生更多的12(S)-羟基二十碳四烯酸（12-HETE），它是花生四烯酸代谢的12-脂氧合酶（12-LO）产物。由于脂氧合酶（LO）途径与氧化应激和动脉粥样硬化的发病机制相关，我们现在在具有人类特征的糖尿病诱导的加速动脉粥样硬化猪模型中研究了体内12-LO的激活情况。
在喂食正常或高脂肪饮食并注射链脲佐菌素的猪中建立动物模型，以产生血脂正常-血糖正常（NLNG）、血脂正常-血糖过高（NLHG）、血脂过高-血糖正常（HLNG）和血脂过高-血糖过高（HLHG）的猪。在猪开始饮食20周后，从关键动脉床获取组织样本，以检测12-LO的表达。
所有HG猪的血清葡萄糖浓度维持在高三倍的水平。HL组出现了动脉粥样硬化，但糖尿病HLHG猪相对于非糖尿病HLNG猪表现出明显加速的动脉粥样硬化（两倍）。免疫染色显示，动脉中12-LO的表达按NLNG、NLHG、HLNG和HLHG的顺序逐渐增加。HLHG猪腹主动脉和冠状动脉中的白细胞型12-LO蛋白（免疫印迹法）以及mRNA表达（竞争性PCR法）显著高于其他三组。此外，在NLHG和HLNG猪的单核细胞中观察到氧化应激增加，而在HLHG猪中氧化应激大大增强。
结论/解读：这些结果与以下假设一致，即12-LO激活在糖尿病和高脂血症导致的加速动脉粥样硬化中起关键作用。
