Troglitazone inhibits alpha(1)-adrenoceptor-induced DNA synthesis in vascular smooth muscle cells

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.