Troglitazone induces apoptosis via the p53 and Gadd45 pathway in vascular smooth muscle cells
Troglitazone induces apoptosis via the p53 and Gadd45 pathway in vascular smooth muscle cells
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DOI：
10.1016/s0014-2999(00)00758-5
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发表时间：
2000-11-03
影响因子：
5
通讯作者：
Hiwada, K
中科院分区：
文献类型：
--
作者：
Okura, T;Nakamura, M;Hiwada, K
噻唑烷二酮类化合物是过氧化物酶体增殖物激活受体γ（peroxisome proliferator-activated receptor，PPAR γ）的激活剂，可诱导多种细胞凋亡。在本研究中，我们研究了噻唑烷二酮类、曲格列酮和吡格列酮对血管平滑肌细胞生长的影响，并确定了曲格列酮除了激活PPAR γ外的特异性作用。亚融合大鼠培养血管平滑肌细胞用或不用PPAR γ激活剂、曲格列酮（1-30 μ M）或吡格列酮（1-30 μ M）处理72小时。处理后，5-30 μ M浓度的曲格列酮显著降低了细胞活力，但吡格列酮没有。用20 μ M曲格列酮处理后48小时，血管平滑肌细胞出现漂浮和收缩。原位DNA标记显示这些细胞的细胞核呈阳性染色，从细胞中提取的基因组DNA显示核小体梯状。c-myc、p21、bax、bcl-2和bcl-x的mRNA表达水平未受曲格列酮治疗的影响。与此相反，沿着诱导血管平滑肌细胞凋亡，p53和Gadd 45的mRNA和蛋白表达水平显着增加，响应曲格列酮。这些结果强烈表明，曲格列酮可以诱导血管平滑肌细胞凋亡，这种作用主要是由激活p53和Gadd 45途径，而不是由激活过氧化物酶体增殖物激活受体γ。(C)2000 Elsevier Science B. V.保留所有权利。
Thiazolidinediones, activators of peroxisome proliferator-activated receptor (PPAR)gamma, have been reported to induce apoptosis in many types of cells. In the present study, we investigated the effects of thiazolidinediones, troglitazone, and pioglitazone on the cell growth of vascular smooth muscle cells, and identified a specific effect of troglitazone in addition to PPAR gamma activation. Subconfluent rat culture Vascular smooth muscle cells were treated with or without PPAR gamma activators, troglitazone (1-30 muM), or pioglitazone (1-30 muM) for 72 h. After treatment, cell viability was significantly reduced by troglitazone in concentration of 5-30 muM but not by pioglitazone. Vascular smooth muscle cells appeared to float and shrink 48 h after treatment with 20 muM of troglitazone. In situ DNA labeling showed that the nuclei of these cells were positively stained, and genomic DNA extracted from the cells showed nucleosomal laddering. Messenger RNA expression levels of c-myc, p21, bax, bcl-2, and bcl-x were not changed by the treatment with troglitazone. In contrast, along with the induction of vascular smooth muscle cell apoptosis, both the mRNA and protein expression levels of p53 and Gadd45 markedly increased in response to troglitazone. These results strongly suggest that troglitazone can induce vascular smooth muscle cell apoptosis and that this effect is caused primarily by activation of the p53 and Gadd45 pathway but not by PPAR gamma activation. (C) 2000 Elsevier Science B.V. All rights reserved.