缬沙坦对兔动脉粥样硬化斑块中ACAT-1和PPAR-γ表达的影响

Effects of valsartan on the expression of acyl-coenzyme A:cholesterol acyltransferase-1 and peroxisome proliferator activated receptor-gamma in experimental atherosclerosis in rabbits

目的研究酰基辅酶A:胆固醇酰基转移酶-1(ACAT-1)和过氧化体增殖物激活型受体γ(PPAR-γ)在动脉粥样硬化斑块中的表达,以及血管紧张素Ⅱ1型受体拮抗剂缬沙坦对ACAT-1和PPAR-γ表达的影响。方法24只雄性日本大耳白兔随机分为对照组、缬沙坦干预组和高胆固醇饮食组,每组8只。喂养12周后,抽取静脉血检测血脂水平,并进行主动脉内膜/中膜比值测定,以RT-PCR和Western blotting方法检测各组主动脉ACAT-1、PPAR-γ mRNA及蛋白的表达。结果高胆固醇饮食组及缬沙坦干预组的血清胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)均无差别(P>0.05),但均高于对照组(P<0.01)。高胆固醇饮食组内膜和内膜/中膜厚度比值显著高于对照组和缬沙坦干预组(P<0.01,P<0.05),而缬沙坦干预组内膜和内膜/中膜厚度比值显著高于对照组(P<0.01)。与对照组比较,高胆固醇饮食组和缬沙坦干预组ACAT-1、PPAR-γ mRNA和蛋白含量显著增加(P<0.01或P<0.05);ACAT-1 mRNA和蛋白在缬沙坦干预组的表达显著低于高胆固醇饮食组(P<0.01或P<0.05),而PPAR-γ mRNA和蛋白在缬沙坦干预组的表达显著高于高胆固醇饮食组(P<0.05)。高胆固醇饮食组和缬沙坦干预组ACAT-1和PPAR-γ mRNA的表达呈明显负相关(P<0.05)。结论缬沙坦可能通过上调PPAR-γ抑制ACAT-1的表达,从而起到抗动脉粥样硬化的作用。

Objective To investigate the effects of valsartan on the expression of acybcoenzyme A： cholesterol acyltransferase-1 （ACAT 1 ） and peroxisome proliferator activated receptor-gamma （PPAR-γ） in atherosclerotic plaques on rabbit aortic wall. Methods Twenty-four male Japanese white rabbits were randomly assigned into three groups （8 each） = control group, valsartan group and high cho lesterol feeding group. All rabbits were fed according to the experimental protocol for 12 weeks. Blood samples were taken from vein for measurement of serum lipids. The ratio of intima/media thickness of the aorta was measured. ACAT-1 mRNA/protein and PPAR-γ mR NA/protein were determined by reverse transcription polymerase chain reaction （RT-PCR） and Western blotting, respectively. Results After 12 weeks, the levels of serum total cholesterol （TC）, triglyeride （TG） and low density lipoprotein cholesterol （LDL-C） in valsartan group and cholesterol group were significantly higher than those in control group （P〈0. 01）, but no significant difference existed between valsartan group and cholesterol group （P〉0. 05）. The intirna thickness and the ratio of intima/media in carotid arteries in cholesterol group were significantly higher than those in control group and valsartan group （ P〈0. 01, P〈0. 05）, while they were significantly higher in valsartan group than those in control group （ P〈0. 01 ）. ACAT-1 mRNA/protein and PPAR -γ mRNA/protein were significantly increased in rabbit aorta in valsartan group and cholesterol group （P〈0. 01, P〈0. 05）. The expression of ACAT-1 mRNA/protein in valsartan group was significantly lower than that in cholesterol group （P〈0. 01, P〈0. 05）, while PPAR- γ mRNA/proteln in valsartan group was higher than that in cholesterol group （P〈0. 05）. A correlation was found between the expression of ACAT-1 mRNA and PPAR-γ mRNA in valsartan group and cholesterol group （ P〈0.05, P〈0. 05）. Condusion Valsartan can inhibit ACAT-1 expression by upregulating the expression of PPAR-γ and may play a role in antiatherogenesis.