摘要
目的探讨瑞舒伐他汀对胰岛素抵抗所致动脉粥样硬化LDLR-/-小鼠AKT、P-AKT表达的影响。方法取6周龄C57BL/6遗传背景的雄性LDL-/-小鼠40只,随机分成5组,每组8只。对照组(NC组):标准饲料;高脂组(HF组):标准饲料+21.1%脂肪;高脂高糖组(HFF组):标准饲料+21.1%脂肪+20%果糖;瑞舒伐他汀干预组(HFFR组):标准饲料+21.1%脂肪+20%果糖+瑞舒伐他汀;甲羟戊酸内酯干预组(HFFRMA组):标准饲料+21.1%脂肪+20%果糖+瑞舒伐他汀+甲羟戊酸内酯。干预12周后处死小鼠,检测血脂、空腹血糖(1BS)、空腹血浆胰岛素水平(FINS),并由此计算稳态模型的胰岛素抵抗指数(HOMA-IR);观察胸腹主动脉和主动脉窦部粥样硬化情况;western印迹法检测各组肝脏、心肌、主动脉弓Akt、p-Akt蛋白的表达并进行比较。结果与NC组相比,HFF组小鼠FBS、FINS、HOMA-IR明显增高(P<0.05),TC、TG、LDL-C显著增高(P<0.05),HDL-C水平明显降低(P<0.05);与HFF组相比,上述指标在HFFR组均得到明显改善(P<0.05);TC与LDL-C在HFF组与HFFRMA组之间未见明显差异(P>0.05)。与其他组相比,HFF组胸腹主动脉和主动脉窦部粥样硬化最严重(P<0.05);与HFF组比较,HFFR组及HFFRMA组粥样硬化面积减少(P<0.05),后两组之间无明显差异。与其他组相比,HFF组小鼠所检测组织Akt、P-Akt的表达明显降低(P<0.05);与HFF组小鼠相比,HFFR组与HFFRMA组中Akt、P-Akt的表达强度显著增高(P<0.05),后两组之间无明显差异(P>0.05)。结论高脂高糖饲料喂养12周后可诱导LDLR-/-小鼠产生胰岛素抵抗,并伴随明显脂质代谢紊乱。胰岛素抵抗可能加速动脉粥样硬化的的发生发展。AKT、P-AKT在胰岛素抵抗LDLR-/-小鼠肝脏、心脏、主动脉弓中的表达受到抑制,表明其可能是胰岛素抵抗形成机制之一。瑞舒伐他汀可通过上调AKT、P-AKT的表达预防胰岛素抵抗的发生,并由此对抗动脉粥样硬化的形成,且此作用独立于降脂作用之外。
Objective To investigate the effect of rosuvastatin on AKT/P-AKT expression in LDLR-/-mice with atherosclerosis induced by insulin resistance. Methods Forty-five LDLR-deficient mice at 6 weeks of age were randomized into 5 groups ( n = 8 in each group) : control group ( NC group ), high fat diet group (HF group ), high fat and high fructose diet group (HFF group ), rosuvastatin intervention groups (HFFR group), rosuvastatin and mevalonic acid intervention group (HFFRMA group). High fat and high fructose diet were given to establish the mouse model with atherosclerosis induced by insulin resistance. The plasma levels of the TC, TG, LDL-C, HDL-C, FBS and FINS were measured after 12 weeks; the morphological of the aorta artery and aorta sinus was examined and the expression of AKT and P-AKT in liver, cardiac muscle, aorta arch was detected. Results Plasma levels of FBS, FINS, HOMA-IR, TC, TG and LDL-C in HFF group were markedly higher than those in other groups ( P 〈 0.05 ), and HDL-C level was significantly decreased ( P 〈 0.05 ). Contrast to HFF group, in HFFR group all above indexes were significantly improved ( P 〈 0.05 ). Plasma TC and LDL-C level showed no significant difference between HFF and HFFRMA group ( P 〉 0.05 ). The area of atherosclerotic plaque in HFF was significantly increased than that of other groups ( P 〈 0.05 ). The area of atherosclerotic plaque in HFFR and HFFRMA group decreased remarkably, and showed no significant difference between the two groups( P 〈 0.05 ). The AKT, P-AKT expressions in HFF group were significantly lower than those in other groups ( P 〈 0. 05 ). Compared with HFF group the expression of AKT and P-AKT in HFFR and HFFRMA groups was up-regulated; there were no differences between HFFR and HFFRMA groups. Conclusion High fat and high fructose diet can induce insulin resistance in LDLR-/- mice. Insulin resistance may accelerate the development of atherosclerosis and inhibit the expression of AKT and P-AKT in liver, cardiac muscle and aorta arch. Rosuvastatin can prevent the development of insulin resistance and atherosclerosis, which may be associated with up-regulation of AKT and P-AKT expression.
出处
《同济大学学报(医学版)》
CAS
2012年第1期37-42,58,共7页
Journal of Tongji University(Medical Science)
基金
浙江省医药卫生科技计划项目(2010KYA179)