Estradiol inhibits hyaluronic acid synthase 1 expression in human vascular smooth muscle cells
Estradiol inhibits hyaluronic acid synthase 1 expression in human vascular smooth muscle cells
复制标题
DOI：
10.1007/s00395-011-0217-5
复制
发表时间：
2011-11-01
影响因子：
9.5
通讯作者：
Fischer, Jens W.
中科院分区：
文献类型：
--
作者：
Freudenberger, Till;Roeck, Katharina;Fischer, Jens W.
流行病学和临床资料表明，雌激素延缓动脉粥样硬化的进展。本研究旨在阐明雌激素对人血管平滑肌细胞（VSMC）的表型调节是否可能涉及对透明质酸基质的影响。在血小板衍生生长因子BB （PDGF-BB）存在或不存在的情况下，血清停药同步VSMC，随后用0.001、0.01、0.1和1 μ M雌二醇（E-2）刺激VSMC 24小时。在PDGF-BB存在和不存在的情况下，E-2降低了透明质酸合成酶（HAS） 1 mrna的表达。相反，HAS2-和has3 - mrna的表达不受影响。这种e -2介导的对HAS1 mrna表达的影响伴随着透明质酸分泌的减少和HA向低分子量的转移，分子筛色谱证实了这一点。雌激素受体(ER) α和β拮抗剂ICI182780消除了HAS1的下调，雌激素受体α激动剂丙基吡唑三醇（PPT）可以模拟HAS1的下调。相反，内质网β激动剂二芳基丙腈（DPN）对HAS1 mrna表达没有影响。为了研究HAS1的下调是否与E-2对人VSMC的表型调节有因果关系，我们进行了慢病毒过表达HAS1的实验。HAS1的过表达消除了对ERK1/2持续磷酸化的抑制，进而抑制了E-2对dna合成的抑制。这项研究首次提供了强有力的证据，证明has1驱动的ha-合成是人类VSMC中E-2的靶标，并且E-2通过ER α依赖性抑制ha-合成来介导其部分抗增殖作用。
Epidemiological and clinical data suggest that estrogen retards the progression of atherosclerosis. This study aims to elucidate whether the phenotypic regulation of human vascular smooth muscle cells (VSMC) by estrogen may involve effects on the hyaluronan matrix. VSMC were synchronized by serum withdrawal and subsequently stimulated with 0.001, 0.01, 0.1 and 1 mu M estradiol (E-2) in the presence or absence of platelet-derived growth factor BB (PDGF-BB) for 24 h. E-2 reduced mRNA-expression of hyaluronic acid synthase (HAS) 1 in the presence and absence of PDGF-BB. In contrast, HAS2- and HAS3-mRNA-expression were not affected. This E-2-mediated effect on HAS1 mRNA-expression was accompanied by reduced hyaluronan secretion and a shift of HA toward lower molecular weight as evidenced by molecular sieve chromatography. The downregulation of HAS1 was abrogated by the estrogen receptor (ER) alpha and beta antagonist ICI182780 and could be mimicked by the ER alpha-agonist propyl-pyrazole triol (PPT). On the contrary, the ER beta-agonist diarylpropionitrile (DPN) had no effect on HAS1 mRNA-expression. To investigate whether the downregulation of HAS1 was causally involved in the phenotypic regulation of human VSMC by E-2, lentiviral overexpression of HAS1 was conducted. Overexpression of HAS1 abrogated the inhibition of sustained ERK1/2 phosphorylation and in turn inhibition of DNA-synthesis by E-2. For the first time this study provides strong evidence that HAS1-driven HA-synthesis is a target of E-2 in human VSMC and that E-2 mediates part of its anti-proliferative effects through an ER alpha-dependent inhibition of HA-synthesis.