E. Nishio et Y. Watanabe, Troglitazone inhibits alpha(1)-adrenoceptor-induced DNA synthesis in vascular smooth muscle cells, EUR J PHARM, 374(1), 1999, pp. 127-135
While vascular smooth muscle cell proliferation is important in hypertensio
n, relatively little is known about the contribution of catecholamines. Nov
el insulin sensitizing agents, thiazolidinediones, have been demonstrated t
o inhibit angiotensin II-, basic fibroblast growth factor (FGF)-induced gro
wth of vascular smooth muscle cells. We hypothesize that these agents might
also inhibit the effect of the stimulation of alpha(1)-adrenoreceptors on
the proliferation of vascular smooth muscle cells. Troglitazone (1-20 mu M)
, a member of the thiazolidinediones, significantly inhibited the stimulati
on of alpha(1)-adrenoreceptor-induced DNA synthesis, c-fos induction and mi
togen-activated protein (MAP)-kinase activation. This effect was associated
with inhibition by troglitazone of the transactivation of the serum respon
se element (SRE), which regulates c-Sos expression. Inhibition of c-Sos ind
uction by troglitazone appeared to occur via blockade of the upstream of MA
P kinase activation in vascular smooth muscle cells. At this dose, troglita
zone inhibited the ternary complex factor (TCF)-dependent activation, which
is regulated by MAP kinase activation, but did not inhibit the TCF-indepen
dent SRE activation. Besides, the degree of the inhibitory effect of trogli
tazone on MAP kinase activation, DNA synthesis, c-fos expression differs. T
his may show that troglitazone work on multiple sites. These results sugges
t that troglitazone is a potent inhibitor of vascular smooth muscle cells p
roliferation through the downregulation of c-fos expression and may be a us
eful agent for prevention of atherosclerosis which is a result of hypertens
ion. (C) 1999 Elsevier Science B.V. All rights reserved.