β-Estradiol

Estradiol is the main sex hormone present in females and also present in males as an active metabolic product of testosterone. It is the major estrogen which impacts on reproductive and organs such as the bones in humans [1].
As a main form of estrogen, estradiol interacts with two estrogen receptors (ER), i.e ERα and ERβ, which exert the effects by diverse signaling pathways that mediate the nongenomic and genomic cases.
With treatment of estradiol, ERβ-specific effects on gene expression have been investigated in three different cell lines lacking expression of endogenous ERα and ERβ, namely U2OS (25), HEK293 (26), and　Hs578T (23) cells. 17 genes of the 76   ERβ-regulated genes were commonly regulated by both ERα and ERβ, suggesting that the transcriptional effects of estradiol via ERα or ERβ are largely distinct in U2OS cells. 95 and 61  genes were identified as ERβ-regulated genes in Hs578T cells and HEK293 cells in a 24-h estradiol treatment, respectively. Only three genes (PTGER4, ENPP2, and DKK1)　commonly regulated in both HEK293 and Hs578T cells, suggesting that ERβ evokes distinct gene responses in different　types of target cells. By using estradiol, new roles of ERβ signaling was established, including protective functions in the epithelial-mesenchymal transition,as well as regulation of cell proliferation in the colon [2].
Animal experiments have shown the protective effects of estrogens in cardiovascular diseases. In mice and in vitro in human aorta endothelial cells, treatment with estradiol increases the expression of mitochondrial superoxide dismutase significantly. Estradiol up-regulates superoxide dismutase by tethering of estrogen receptor to Sp1 and the increased binding of Sp1 to GC-box on the superoxide dismutase promoter, where ERα responses estradiol-mediated activation of gene, and ERβ maintains a level of basal gene expression. Investigation of the reduction in PS levels caused by E2 in HepG2-ERα cells showed E2 repressed the production of mRNA and antigen of PS. In addition, E2 might repress PROS1 transcription depending upon ERα-Sp1 recruiting transcriptional repressors in HepG2-ERα cells and, the high levels of E2 resulting in reduced levels of plasma PS would be a risk for deep venous thrombosis in pregnant women [1,3].

雌二醇是存在于女性体内的主要性激素，也作为睾酮的活性代谢产物存在于男性体内。它是影响生殖和人体骨骼等器官的主要雌激素[1]。

作为雌激素的主要形式，雌二醇与两种雌激素受体（ER）相互作用，即ERα和ERβ，这两种受体通过介导非基因组和基因组病例的不同信号通路发挥作用。

通过雌二醇处理，研究了三种缺乏内源性ERα和ERβ表达的不同细胞系，即U2OS（25）、HEK293（26）和Hs578T（23）细胞中ERβ对基因表达的特异性影响。76个ERβ调控基因中有17个基因共同受到ERα和ERβ的调控，这表明雌二醇通过ERα或ERβ的转录作用在U2OS细胞中有很大不同。在24小时雌二醇处理的Hs578T细胞和HEK293细胞中分别鉴定出95和61个基因为ERβ调节基因。只有三个基因（PTGER4、ENPP2和DKK1）在HEK293和Hs578T细胞中共同调控，这表明ERβ在不同类型的靶细胞中引起不同的基因反应。通过使用雌二醇，建立了ERβ信号传导的新作用，包括在上皮-间质转化中的保护功能，以及对结肠细胞增殖的调节[2]。

动物实验表明雌激素对心血管疾病具有保护作用。在小鼠和体外人主动脉内皮细胞中，雌二醇处理显著增加线粒体超氧化物歧化酶的表达。雌二醇通过雌激素受体与Sp1的结合以及Sp1与超氧化物歧化酶启动子上GC盒的结合增加来上调超氧化物歧化酶，其中ERα响应雌二醇介导的基因激活，而ERβ维持基础基因表达水平。对E2在HepG2 ERα细胞中引起的PS水平降低的研究表明，E2抑制PS的mRNA和抗原的产生。此外，E2可能抑制PROS1的转录，这取决于HepG2内质网α细胞中ERα-Sp1募集转录抑制因子，高水平的E2导致血浆PS水平降低，这将是孕妇深静脉血栓形成的风险[1,3]。

References:
[1]. Liu ZY, Gou YL, Zhang HY, et al. Estradiol improves cardiovascular function through up-regulation of SOD2 on vascular wall. Redox Biology, 2014, 3: 88-99.
[2]. Zhao CY, Dahlman-Wright K, Gustafsson J. Estrogen signaling via estrogen
receptor β*. The Journal Of Biological Chemistry, 2010, 51: 39575–39579.
[3]. Suzuki A, Sanda N, Miyawaki Y, et al. Down-regulation of pros1 gene expression by 17 beta-estradiol via estrogen receptor alpha (er alpha)-sp1 interaction recruiting receptor-interacting protein 140 and the corepressor-hdac3 complex. Journal Of Biological Chemistry, 2010, 285(18): 13444-13453.