Troglitazone inhibits alpha1-adrenoceptor-induced DNA synthesis in vascular smooth muscle cells.
While vascular smooth muscle cell proliferation is important in hypertension, relatively little is known about the contribution of catecholamines. Novel insulin sensitizing agents, thiazolidinediones, have been demonstrated to inhibit angiotensin II-, basic fibroblast growth factor (FGF)-induced growth of vascular smooth muscle cells. We hypothesize that these agents might also inhibit the effect of the stimulation of alpha1-adrenoreceptors on the proliferation of vascular smooth muscle cells. Troglitazone (1-20 microM), a member of the thiazolidinediones, significantly inhibited the stimulation of alpha1-adrenoreceptor-induced DNA synthesis, c-fos induction and mitogen-activated protein (MAP)-kinase activation. This effect was associated with inhibition by troglitazone of the transactivation of the serum response element (SRE), which regulates c-fos expression. Inhibition of c-fos induction by troglitazone appeared to occur via blockade of the upstream of MAP kinase activation in vascular smooth muscle cells. At this dose, troglitazone inhibited the ternary complex factor (TCF)-dependent activation, which is regulated by MAP kinase activation, but did not inhibit the TCF-independent SRE activation. Besides, the degree of the inhibitory effect of troglitazone on MAP kinase activation, DNA synthesis, c-fos expression differs. This may show that troglitazone work on multiple sites. These results suggest that troglitazone is a potent inhibitor of vascular smooth muscle cells proliferation through the downregulation of c-fos expression and may be a useful agent for prevention of atherosclerosis which is a result of hypertension.
Nishio
E
E
Department of Pharmacology, National Defense Medical College, Tokorozawa, Saitama, Japan.
Watanabe
Y
Y
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000187:drug effects; D016762:Genes, fos; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009687:Nuclear Proteins / Q000187:drug effects; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects* / Q000502:physiology; D020218:Response Elements / Q000187:drug effects; D026362:Serum Response Factor; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D015533:Transcriptional Activation / Q000187:drug effects; D000077288:Troglitazone; D010738:Type C Phospholipases / Q000378:metabolism
D002839:Chromans; D004268:DNA-Binding Proteins; D007004:Hypoglycemic Agents; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D018340:Receptors, Adrenergic, alpha-1; D026362:Serum Response Factor; D013844:Thiazoles; D045162:Thiazolidinediones; D010656:Phenylephrine; D004247:DNA; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010738:Type C Phospholipases; D000077288:Troglitazone