Nishio E, Watanabe Y
Department of Pharmacology, National Defense Medical College, Tokorozawa, Saitama, Japan.
Eur J Pharmacol. 1999 Jun 11;374(1):127-35. doi: 10.1016/s0014-2999(99)00271-x.
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.
虽然血管平滑肌细胞增殖在高血压中很重要，但关于儿茶酚胺的作用相对知之甚少。新型胰岛素增敏剂噻唑烷二酮已被证明可抑制血管紧张素II、碱性成纤维细胞生长因子（FGF）诱导的血管平滑肌细胞生长。我们假设这些药物也可能抑制α1 - 肾上腺素能受体刺激对血管平滑肌细胞增殖的影响。噻唑烷二酮类药物之一的曲格列酮（1 - 20微摩尔）显著抑制α1 - 肾上腺素能受体诱导的DNA合成、c - fos诱导和丝裂原活化蛋白（MAP）激酶活化。这种作用与曲格列酮抑制血清反应元件（SRE）的反式激活有关，SRE可调节c - fos表达。曲格列酮对c - fos诱导的抑制似乎是通过阻断血管平滑肌细胞中MAP激酶活化的上游来实现的。在此剂量下，曲格列酮抑制由MAP激酶活化调节的三元复合因子（TCF）依赖性活化，但不抑制不依赖TCF的SRE活化。此外，曲格列酮对MAP激酶活化、DNA合成、c - fos表达的抑制作用程度不同。这可能表明曲格列酮作用于多个位点。这些结果表明，曲格列酮通过下调c - fos表达是血管平滑肌细胞增殖的有效抑制剂，可能是预防高血压所致动脉粥样硬化的有用药物。
