17β-Estradiol inhibits TNF-α-induced proliferation and migration of vascular smooth muscle cells via suppression of TRAIL

Abstract

Atherosclerosis is an inflammatory disease and involves migration of vascular smooth muscle cells (VSMCs). Estrogen inhibits VSMCs migration, while the underlying mechanism remains to be revealed. Recent years, there is emerging evidence showing that TNF-related apoptosis-inducing ligand (TRAIL) increases proliferation and migration of VSMCs. In this study, we investigated the regulatory effect of estrogen on TRAIL expression in VSMCs. TNF-α greatly enhanced TRAIL protein expression and stimulated VSMCs proliferation and migration. This effect was partially inhibited by the addition of TRAIL neutralizing antibody, suggesting that TRAIL is important in TNF-α-induced migration. 17β-estradiol (E2) inhibited TRAIL expression under TNF-α stimulation in a time- and concentration-dependent manner. This effect was was mimicked by ERα agonist 4′,4″,4‴-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT), but not ERβ agonist 2,3-bis-(4-hydroxyphenyl)-propionitrile (DPN), indicating that ERα is involved in this action. TNF-α led to nuclear factor kappa B (NF-κB) p65 phosphorylation and the inhibitor pyrrolidine dithiocarbama (PDTC) inhibited TRAIL expression, suggesting that NF-κB signaling is crucial for TARIL production. E2 suppressed p65 phosphorylation in VSMCs and the overexpression of p65 subunit reversed the inhibitory effect of E2 on TRAIL expression and cell proliferation and migration. Taken together, our results indicate that E2 inhibits VSMCs proliferation and migration by downregulation of TRAIL expression via suppression of NF-κB pathway.

Chinese abstract

动脉粥样硬化是一种炎症性疾病，其机制包括血管平滑肌细胞（VSMCs）的迁移。雌激素可抑制血管平滑肌细胞的迁移，但是潜在机制有待研究。近年来，不断出现的证据表明，肿瘤坏死因子相关凋亡诱导配体（TRAIL）增加血管平滑肌细胞的增殖和迁移。在这项研究中，我们研究了雌激素对TRAIL在血管平滑肌细胞表达的调节作用。肿瘤坏死因子-α极大的增强了TRAIL蛋白的表达并刺激血管平滑肌细胞的增殖和迁移。加入TRAIL中和抗体后，这种作用被部分抑制，这表明TRAIL在TNF-α介导的迁移中很重要。17β雌二醇（E2）抑制TNF-α刺激下TRAIL的表达，这种抑制呈时间和浓度依赖性。这种影响能够被雌激素受体α激动剂4’,4”,4”--(4-丙基-[1氢]- 吡唑-1,3,5-三基) 三苯酚 (PPT)所模拟，但不能被雌激素受体β激动剂2，3-双-（4-羟丙基）-丙腈所模拟，表明是雌激素受体α参与了这一过程。肿瘤坏死因子-α导致核因子kB (NF-kB)p65磷酸化，NF-kB的抑制剂吡咯烷二硫代氨基甲酸盐（PDTC）抑制TRAIL的表达，表明NF-κB信号通路对TARIL的表达至关重要。E2抑制血管平滑肌中的p65的磷酸化和p65亚基的过度表达，反应了E2对TRAIL的表达以及细胞的增值和迁移的抑制作用。综上所述，我们的研究结果表明，E2通过对抑制NF-kB通路实现对TRAIL表达的降调节，进而抑制VSMCs的增殖和迁移。

• 17β-Estradiol
• migration
• nuclear factor kappa B
• TNF-related apoptosis-inducing ligand
• vascular smooth muscle cell