过氧化物酶增生物激活受体γ在ox-LDL诱导的血管平滑肌细胞凋亡中的作用

Effect of Peroxisome Proliferator-activated Receptor-γ on the VSMCs Apoptosis Induced by Oxidized LDL

目的探讨氧化修饰的低密度脂蛋白(ox-LDL)诱导血管平滑肌细胞(VSMC)凋亡的机制和过氧化物酶增生物激活受体(PPARγ)特异性激动剂对培养的VSMC凋亡的影响,评价PPARγ在动脉粥样硬化(AS)发生和发展中的作用。方法培养的鼠VSMC中加入不同浓度ox-LDL和PPARγ的两种激动剂———环格列酮(ciglitazone)和15脱氧-前列腺素J2(15d-PGJ2),孵育24 h,用透射电镜观察细胞凋亡的特征性形态学改变;流式细胞仪测定细胞凋亡率。另外,在给予ox-LDL、ciglitazone和15d-PGJ2的同时,加入PPARγ的抑制剂PGF2α,比较未加和加入抑制剂PGF2α组之间VSMC的形态学改变、凋亡率。结果ox-LDL及ciglitazone、15d-PGJ2均可诱导VSMC凋亡,且凋亡率增加与3种物质的剂量变化有关;PGF2α能降低ox-LDL、ciglitazone和15d-PGJ2诱导的VSMC凋亡率。结论PPARγ内源性的配体ox-LDL诱导VSMC凋亡的作用是通过激活PPARγ途径实现的;PPARγ内源性的配体和特异性激动剂过度激活PPARγ途径有促进细胞凋亡而导致AS斑块不稳定性增加的可能。

Objective To explore the mechanism of VSMCs apoptosis induced by ox-LDL and the effects of PPARγ specific agonist on the apoptosis of cultured VSMCs, and evaluate the role of PPARγ in atherosclerosis. Methods Rat aorta smooth muscle cells were isolated and cultured in DMEM containing 10 % FBS, Ox-LDL, ciglitazone and 15-deoxy-△^12.14-PGJ2 were added into the medium for 24, 24 and 20 h respectively. Under transmission electron microscopy, the morphological changes in apoptosis were observed. By using flow cytometry, the apoptotic rate was detected. After addition of ox-LDL, ciglitazone, 15d-PGJ2 and PGF2α simultaneously, morphological changes and apoptosis rate were observed. Results All ox-LDL, ciglita- zone and 15d-PGJ2 could induce the apoptosis of VSMCs in a dose-dependent manner, PGF2, could reduce the apoptosis rate of VSMCs mediated by ox-LDL, ciglitazone and 15d-PGJ2. Conclusion Ox-LDL induces the apoptosis of VSMCs at least in part through the activation of PPARγ, Ciglitazone and 15d-PGJ2 as the agonists of PPARγ can also induce the apoptosis of VSMCs in a PPARγ-dependent way, The results suggest that the activator of PPARγ may have bad effects on the progress of atherosclerotic disease via reducing the stability of plaques.