Effect of probucol on serum lipids, atherosclerosis and toxicology in fat-fed LDL receptor deficient    mice

    尽管最近开发出了许多转基因动脉粥样硬化小鼠模型，但其对于降血脂和抗动脉硬化药物的反应还了解甚少。本实验研究了抗高胆固醇血症和抗动脉粥样硬化药物普罗布考对脂肪饲养低密度脂蛋白受体缺失小鼠的血清脂质，脂蛋白和动脉粥样硬化的影响。与以往研究小鼠饮食中普罗布考添加剂量相近，普罗布考在饮食中添加0.2%和1%分别降低血清胆固醇26%和37%，分别降低血清甘油三酯33%和47%。血清胆固醇和甘油三酯的减少主要是与VLDL和/或乳糜微粒中脂质的减少有关。尽管血清中的脂质发生了潜在有利的变化，但普罗布考治疗小鼠的主动脉粥样硬化损伤面积未发生改变。给药12周后，大部分普罗布考治疗小鼠因水肿发生四肢和尾部肿胀。对普罗布考治疗的小鼠心脏基部进行组织学检验发现其网状内皮细胞和间质细胞中有脂滴存在。脂质沉积使间质亚急性炎症细胞渗透。普罗布考导致的水肿可能是由于心脏基部间质脂质沉积和炎症以及大动脉窦区动脉粥样硬化重大损伤所引起的。

    Although numerous transgenic mouse models for atherosclerosis have been developed recently, little is known about     their response to hypolipidaemic or anti-atherosclerotic agents. We investigated the effect of the known                 hypocholesterolaemic and anti-atherosclerotic drug probucol on serum lipids, lipoproteins and atherosclerosis in fat-fed low density lipoprotein (LDL) receptor deficient mice.Probucol at doses of 0.2 and 1% in the diet which are similar to    those used in the mouse by other investigators reduced serum cholesterol by 26 and 37%, respectively. Probucol also      reduced serum triglyceride levels by 33 and 47% at doses of 0.2 and 1%, respectively. The decrease in serum cholesterol  and triglycerides was mainly due to a decrease of these lipids in VLDL and or chylomicrons. Despite these potentially    beneficial changes in serum lipids atherosclerotic lesion areas in the aortic root were unchanged in the probucol treated mice. After 12 weeks treatment most of the mice receiving probucol had swollen feet and tails due to oedema.Histological examination of the base of the hearts from the probucol treated mice revealed lipid droplets within the                  reticuloendothelial and other interstitial cells. There was also an interstitial subacute inflammatory cell infiltration associated with the lipid deposition. The oedema induced by probucol could be the result of cardiac insufficiency due to interstitial lipidosis and inflammation in the base of the heart together with  the extensive atherosclerotic lesions in the aortic sinus.