Troglitazone and rosiglitazone induce apoptosis of vascular smooth muscle cells through an extracellular signal-regulated kinase-independent pathway

被引：0

作者：

Gouni-Berthold I. ^{[1
]}

Berthold H.K. ^{[1
]}

Weber A.-A. ^{[2
]}

Ko Y. ^{[1
]}

Seul C. ^{[1
]}

Vetter H. ^{[1
]}

Sachinidis A. ^{[1
]}

机构：

[1] Medizinische Universitats-Poliklinik, 53111 Bonn

[2] Institut fur Pharmakologie, Heinrich-Heine-Universitat Dusseldorf, Dusseldorf

来源：

Naunyn-Schmiedeberg's Archives of Pharmacology | 2001年 / 363卷 / 2期

关键词：

Apoptosis; Oral antidiabetics; Oral hypoglycemic agents; Peroxisome proliferator-activated receptor γ; Rosiglitazone; Signal-regulated response kinases; Smooth muscle; Thiazolidinediones; Troglitazone;

D O I：

10.1007/s002100000352

中图分类号：

学科分类号：

摘要：

Recent evidence suggests that apoptosis may be involved in the control of vascular smooth muscle cell (VSMC) number in atherosclerotic lesions. The peroxisome proliferator-activated receptor γ (PPARγ) ligands thiazolidinediones have been reported to induce apoptosis in macrophages and in a variety of tumor cell lines. To evaluate whether these agents also induce apoptosis in VSMC, cultured rat VSMC were treated with increasing doses of the thiazolidinedione analogues troglitazone (TRO) and rosiglitazone (RSG). Both ligands induced cell death in a (concentration-dependent manner (EC)50 (12.1±3.3) μM and 1.43±0.39 μM, respectively), causing almost complete cell death at the highest concentrations (100 μM and 10 μM for TRO and RSG, respectively), along with an expected parallel decrease in [3H]thymidine uptake into cell DNA (EC)50 6.7±2.4 μM and 0.75±0.19 μM, respectively). The cell count was determined by the coulter counter principle. Furthermore two apoptotic markers were measured, the caspase 3 activity and the cytoplasmic histone-associated DNA fragments, both of which were significantly increased when the aforementioned high concentrations were used. This indicates that apoptosis is involved in the TRO- and RSG-induced VSMC growth suppression. The same concentrations of TRO and RSG caused an unexpected stimulation of the extracellular signal-regulated response kinases 1 and 2 (ERK1/2) and stimulated the p38 mitogenic-activated protein (MAP) kinase as determined by Western blotting. In order to establish whether the proapoptotic effects of TRO and RSG are mediated through ERK1/2 activation, we used the selective MAP kinase kinase (MEK) inhibitor PD98059 (20 μM), which suppressed the TRO- and RSG-induced ERK1/2 activation but did not abolish their proapoptotic effects. We conclude that the thiazolidinedione analogues TRO and RSG induce cell death due to apoptosis in VSMC through an ERK1/2-independent pathway.

引用

页码：215 / 221

页数：6

共 31 条

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