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Troglitazone inhibits vascular smooth muscle cell growth and intimal hyperplasia

Authors :
William P. Meehan
David P. Faxon
Willa A. Hsueh
Ronald E. Law
William D. Coats
D A Wuthrich
X P Xi
Kristof Graf
Source :
Journal of Clinical Investigation. 98:1897-1905
Publication Year :
1996
Publisher :
American Society for Clinical Investigation, 1996.

Abstract

Vascular smooth muscle cell (VSMC) proliferation and mi- gration are responses to arterial injury that are highly im- portant to the processes of restenosis and atherosclerosis. In the arterial balloon injury model in the rat, platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) are induced in the vessel wall and regulate these VSMC activities. Novel insulin sensitizing agents, thiazo- lidinediones, have been demonstrated to inhibit insulin and epidermal growth factor-induced growth of VSMCs. We hypothesized that these agents might also inhibit the effect of PDGF and bFGF on cultured VSMCs and intimal hyper- plasia in vivo. Troglitazone (1 m M), a member of the thiazo- lidinedione class, produced a near complete inhibition of both bFGF-induced DNA synthesis as measured by bro- modeoxyuridine incorporation (6.5 6 3.9 vs. 17.6 6 4.3% cells labeled, P , 0.05) and c-fos induction. This effect was asso- ciated with an inhibition (by 73 6 4%, P , 0.01) by troglita- zone of the transactivation of the serum response element, which regulates c-fos expression. Inhibition of c-fos induc- tion by troglitazone appeared to occur via a blockade of the MAP kinase pathway at a point downstream of MAP kinase activation by MAP kinase kinase. At this dose, troglitazone also inhibited PDGF-BB-directed migration of VSMC (by 70 6 6%, P , 0.01). These in vitro effects were operative in vivo. Quantitative image analysis revealed that troglita- zone-treated rats had 62% ( P , 0.001) less neointima/media area ratio 14 d after balloon injury of the aorta compared with injured rats that received no troglitazone. These results suggest troglitazone is a potent inhibitor of VSMC prolifera- tion and migration and, thus, may be a useful agent to pre- vent restenosis and possibly atherosclerosis. ( J. Clin. Invest. 1996. 98:1897-1905.) Key words: restenosisplatelet- derived growth factorbasic fibroblast growth factorc-fos • MAP kinase

Details

ISSN :
00219738
Volume :
98
Database :
OpenAIRE
Journal :
Journal of Clinical Investigation
Accession number :
edsair.doi.dedup.....655efb0e9eb0b423e677435b0ed46a29
Full Text :
https://doi.org/10.1172/jci118991