瑞舒伐他汀与吡格列酮对糖尿病大鼠早期动脉粥样硬化影响

THE EFFECTS OF ROSUVASTATIN AND PIOGLITAZONE ON DIABETIC RATS WITH EARLY ATHEROSCLEROSIS

目的观察选择性羟甲戊二酰还原酶抑制剂瑞舒伐他汀(Rosu)联合过氧化物酶体增殖物激活受体γ(PPARγ)激动剂吡格列酮(Piog)对糖尿病大鼠早期动脉粥样硬化(AS)形成的影响,并探讨其作用机制。方法将雄性Wister大鼠随机分为5组(每组10只)。正常对照(NC)组:普通饮食,并给予枸橼酸缓冲液及生理盐水作对照。采用高糖高脂饮食法制作糖尿病大鼠AS模型成模后4周,模型(M)组:腹腔注射50mg/kg链脲佐菌素及生理盐水作对照;Rosu组:腹腔注射50mg/kg链脲佐菌素+Rosu 5mg/(kg.d)灌胃;Piog组:腹腔注射50mg/kg链脲佐菌素+Piog 5mg/(kg.d)灌胃;Rosu联合Piog组(R&P组):腹腔注射50mg/kg链脲佐菌素+Piog及Ro-su各5mg/(kg.d)灌胃。16周后取血检测各组大鼠总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白胆固醇(LDL-C)、稳态血糖(BG)与空腹血胰岛素(PGI)水平,采用免疫组织化学方法检测主动脉血管壁基质金属蛋白酶-9(MMP-9)及PPARγ的表达水平。结果 Rosu组、Piog组、R&P组、M组TC、TG、LDL-C及BG较NC组明显升高(F=66.89～273.24,q=3.93-46.60,P<0.05),前3组较M组明显降低(q=5.72～26.02,P<0.05),R&P组与Piog组及Rosu组LDL-C水平比较差异有显著性(q=3.93-29.85,P<0.05);Rosu组、Piog组及R&P组MMP-9、PPARγ阳性细胞率和浸润的单核细胞数明显高于NC组(F=29.39～593.33,q=5.03～59.62,P<0.05),而低于M组(q=3.14～54.89,P<0.05),R&P组与Rosu组、R&P组与Piog组比较,MMP-9、PPARγ表达水平和浸润的单核细胞数明显降低,差异有显著性(q=2.85～24.72,P<0.05)。结论 Rosu可降低大鼠TC、TG、LDL-C及MMP-9表达;Piog可降低大鼠LDL-C、BG水平,减轻胰岛素抵抗,降低MMP-9、PPARγ的表达;而两者联用可更有效降低血LDL-C及MMP-9、PPARγ的表达,防止AS的形成。

Objective To study the effect of selective HMG-CoA reductase inhibitor Rosuvastatin combined with peroxi some proliferator-activated receptor γ （PPARγ） agonist Pioglitazone on diabetic rats with early atherosclerosis and explore its mechanism of action. Methods Fifty male Wistar rats were evenly randomized to five group as follows： normal control group （ NC）, full diet, citrate buffer and normal saline were given. A model of diabetic rat with atherosclerosis （AS） was created by highsugar and high-fat diet. Four weeks after the creation of models, the following managements were done： in model group, intraperitoneal injection of streptozotocin 50 mg/kg and normal saline carried out to serve as control; in Rosuvastatin group, streptozotocin, 50 mg/kg, was intraperitoneally injected and Rosuvastatin, 5 mg/（kg · d） intragastrically ; in Pioglitazone group ： streptozoto cin 50 mg/kg intraperitoneal injection and Pioglitazone, 5 mg/（kg· d）, intragastrically; in Rosuvastatin combined Pioglitazone group （R＆P）, streptozotocin 50 mg/kg intraperitoneal injection and intragastric medication of Pioglitazone and Rosuvastatin, 5 mg/（kg· d）, respectively. After 16 weeks, TC, TG, LDL-C, BG and PGI were measured. Immunohistochemistry was used to analyze the expressions of MMP-9 and PPARγ receptors. Results The levels of TC, TG, LDL-C and BG in Rosuvastatin group, Pioglitazone group and R＆P group were markedly higher than that of NC （F=66.89-273.24;q=3.93-46.60;P〈0.05）, but lower than that of model group （q=5.72-26.02,P〈0.05）, the differences of the levels of LDLC between R＆P group and Rosu vastatin group as well as Pioglitazone group were significant （q= 3.93-29.85, P〈0.05）. The positive MMP-9 and PPARγ expressions and infiltration of mononuclear cells in Rosuvastatin group,Pioglitazone group and R＆P group were markedly higher thanthat of NC （F=29.39-593.33;q=5.03-59. 62;P〈0.05）, but lower than that of DM model group （q：3.14--54.89,P〈0.05）, A comparison of MMP-9, PPARγ and infiltration of mononuclear cells between R＆P group and Rosuvastatin group, and between R＆P andPioglitazone groups showed the differences were significant （q=2. 85-24. 72, P〈0.05）. Conclusion Rosuvastatin can reduce the expression levels of T, TG, LDL-C and MMP-9 in rats, and pioglitazone can reduce the levels of LDL-C and BG as well as insulin resistance, decrease the expressions of MMP-9 and PPARγ. A combination of Rosuvastatin with Pioglitazone can more effectively lower blood LDL-C concentration and inhibit the expressions of MMP-9 and PPARγ, preventing the formation of atheroselerosis.