PPAR-α/γ激动剂对代谢综合征大鼠模型心室重构中MMP-9表达和TGF-β/Smads通路的影响

Effect of PPAR-α/γ agonist agent on the expression of MMP-9 and TGF-β/Smads pathway in ventricular remodeling of rat model of metabolic syndrome

目的探讨PPAR-α/γ激动剂对代谢综合征(Metabolic syndrome,MS)大鼠模型心室重构中MMP-9表达和TGF-βSmads通路的影响及意义。方法 60%果糖饮食喂养雄性SD大鼠构建MS大鼠模型并随机分组:模型对照组(MC组,n=10)、非诺贝特组(FEN组,n=11)、吡格列酮组(PIO组,n=10)、非诺贝特+匹格列酮组(FEN+PIO组,n=11),正常对照组(NC组,n=6)。NC组大鼠用普通标准饲料喂养,FEN组和PIO组大鼠分别加用非诺贝特30 mg/(kg·d)及吡格列酮3 mg/(kg·d)灌胃;FEN+PIO组大鼠加非诺贝特30 mg/(kg·d)和吡格列酮3 mg/(kg·d)灌胃,干预4周后RT-PCR方法检测PPAR-α/γmRNA水平,免疫组化方法检测MMP-9和TGF-β1蛋白表达。结果 MC组PPAR-α/γmRNA的结果均低于NC组,差异具有统计学意义(P<0.05)。FEN组PPAR-αmRNA(0.59±0.03)和PPAR-γmRNA(0.61±0.03)均高于MC组,低于NC组,差异具有统计学意义(P<0.05);PIO组PPAR-α(0.57±0.04)和PPAR-γmRNA(0.54±0.02)均低于NC组,且低于MC组,具有统计学意义(P<0.05);FEN+PIO组PPAR-αmRNA(0.63±0.02)和PPAR-γmRNA(0.67±0.03)均高于MC组,差异具有统计学意义(P<0.05);MMP-9和TGF-β1在各组大鼠心肌均有表达。与NC组大鼠比较,MC组、FEN组、PIO组和FEN+PIO组大鼠心肌表达MMP-9和TGF-β1/Smads蛋白明显增强,差异具有统计学意义(P<0.05);与MC组比较,FEN组、PIO组、FEN+PIO组大鼠心肌表达MMP-9和TGF-β1/Smads蛋白均减弱,差异具有统计学意义(P<0.05);FEN+PIO组大鼠心肌表达MMP-9 OD值(0.43±0.04)低于FEN组和PIO组,差异具有统计学意义(P<0.05)。结论 FEN和PIO均上调了PPAR-α/γmRNA表达、使TGF-β1和MMP-9蛋白明显下降,对心室重构改善有明显的意义,其可能通过TGF-β/smads通路发挥作用。

Objective To study the effect of PPAR-α/γ agonist agent on on the expression of MMP-9 and TGF-β/ Smads pathway in ventricular remodeling of rat model of metabolic syndrome （MS）. Methods Male SD rats were fed with 60% fructose to construct MS rat models, which were divided into five groups： model control group （MC group, n= 10）, fenofibmte group （FEN group, n=11）, pioglitazone group （PIO group, n=10）, fenofibrate＋pioglitazone group （FEN＋ PIO group, n=ll）, normal control group （NC group, n=6）. The rats in NC group were fed with common standard; rats in FEN group and PIO group were added fenofibrate 30 mg/（kg, d） and pioglitazone 3 mg/（kg, d） gavage, respectively; rats in FEN＋PIO group were added fenofibmte 30 mg/（kg.d） and pioglitazone 3 mg/（kg·d） gavage. Four weeks after the intervention, RT-PCR was applied to detect the PPAR-α/γ mRNA level, and immunohistochernical method was performed to detect the expression of MMP-9 and TGF--β protein. Results PPAR-α/γ mRNA level of MC group were lower than those of NC group, and the difference was significant （P〈0.05）. In FEN group, PPAR-α mRNA level （0.59±0.03） and PPAR--T mRNA level （0.61±0.03） were significantly higher than those of MC group, while significantly lower than that of NC group （P〈0.05）. In PIO group, PPAR-α （0.57±0.04） and PPAR-γ mRNA level （0.54±0.02） were significantly lower than those of NC group and significantly lower than MC group （P〈0.05）. PPAR-a mRNA level （0.63 ± 0.02） and PPAR-γ mRNA level （0.674-0.03） in FEN＋PIO group were significantly higher than those of MC group. MMP-9 and TGF-β Smads expression of MC group, FEN group, PIO group and FEN＋PIO group rats myocardial expression were significantly higher than NC group （P〈0.05）. Compared with MC group, FEN group, MMP-9 and TGF-β/Smads protein expression of PIO group, FEN＋PIO group were significantly decreased （P〈0.05）. MMP-9 expression level of FEN＋PIO group in rat myocardial （0.43±0.04） was significantly lower than that of FEN group and PIO group （P〈0.05）. Conclusion FEN and PIO could up-regulate PPAR-α/γ mRNA expression and decrease TGF-β and MMP-9 protein expression, which improves ventricular remodeling obviously. It may play a role by TGF-β Smads pathway.