Troglitazone Induces Apoptosis via the p53 and Gadd45 Pathway in Vascular Smooth Muscle Cells

Eur J Pharmacol. 2000 Nov 3;407(3):227-35. doi: 10.1016/s0014-2999(00)00758-5.

Abstract

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 PPARgamma activation. Subconfluent rat culture vascular smooth muscle cells were treated with or without PPARgamma activators, troglitazone (1-30 microM), or pioglitazone (1-30 microM) for 72 h. After treatment, cell viability was significantly reduced by troglitazone in concentrations of 5-30 microM but not by pioglitazone. Vascular smooth muscle cells appeared to float and shrink 48 h after treatment with 20 microM 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 PPARgamma activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cells, Cultured
  • Chromans / pharmacology*
  • Gene Expression / drug effects
  • Gene Expression / physiology
  • Hypoglycemic Agents / pharmacology
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / drug effects*
  • Muscle, Smooth, Vascular / metabolism
  • Pioglitazone
  • Platelet Aggregation Inhibitors / pharmacology*
  • Proteins / drug effects*
  • Proteins / metabolism
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Cytoplasmic and Nuclear / drug effects
  • Receptors, Cytoplasmic and Nuclear / physiology
  • Thiazoles / pharmacology*
  • Thiazolidinediones*
  • Transcription Factors / drug effects
  • Transcription Factors / physiology
  • Troglitazone
  • Tumor Suppressor Protein p53 / drug effects*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Chromans
  • GADD45 protein
  • Hypoglycemic Agents
  • Intracellular Signaling Peptides and Proteins
  • Platelet Aggregation Inhibitors
  • Proteins
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Thiazoles
  • Thiazolidinediones
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Troglitazone
  • Pioglitazone