MiR-22/Sp-1 Links Estrogens With the Up-Regulation of Cystathionine γ-Lyase in Myocardium, Which Contributes to Estrogenic Cardioprotection Against Oxidative Stress.
MiR-22/Sp-1 Links Estrogens With the Up-Regulation of Cystathionine γ-Lyase in Myocardium, Which Contributes to Estrogenic Cardioprotection Against Oxidative Stress.
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DOI：
10.1210/en.2014-1362
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发表时间：
2015-03
期刊：
影响因子：
4.8
通讯作者：
Long Wang;Zhiping Tang;Wei Zhao;Bing Cong;Jianqiang Lu;Xiao-lu Tang;Xiao-Han Li;Xiaoyan Zhu;X. Ni
中科院分区：
文献类型：
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作者：
Long Wang;Zhiping Tang;Wei Zhao;Bing Cong;Jianqiang Lu;Xiao-lu Tang;Xiao-Han Li;Xiaoyan Zhu;X. Ni
硫化氢主要通过胱硫醚-γ-裂解酶（CSE）在心肌中产生，具有心脏保护作用。我们的前期研究表明雌激素可增强雌性大鼠心肌CSE的表达。本研究旨在探讨雌激素调节CSE表达的机制，特别是阐明雌激素受体亚型和负责雌激素效应的转录因子的作用。我们发现CSE抑制剂或CSE小干扰RNA都减弱了17β-雌二醇（E2）对原代培养的新生心肌细胞H2 O2和缺氧/复氧损伤的保护作用。E2通过雌激素受体（ER）-α刺激体外培养的心肌细胞和体内雌性小鼠心肌中CSE的表达。在大鼠CSE启动子中鉴定出特异性蛋白-1（Sp-1）共有位点，并发现其介导E2诱导的CSE表达。E2增加去卵巢大鼠心肌ERα和Sp-1表达，抑制microRNA（miR）-22表达。在原代心肌细胞中，E2通过ERα介导的miR-22下调来刺激Sp-1表达。证实miR-22靶向ERα和Sp-1。在卵巢切除大鼠心肌中，miR-22水平与CSE、ERα、Sp-1和抗氧化生物标志物呈负相关，与氧化生物标志物呈正相关。综上所述，本研究表明雌激素通过ERα介导的心肌细胞miR-22的下调来刺激Sp-1，导致CSE的上调，这反过来又导致抗氧化防御的增加。ERα、miR-22和Sp-1的相互作用可能在雌性大鼠心肌氧化应激状态的控制中发挥关键作用。
Hydrogen sulfide, generated in the myocardium predominantly via cystathionine-γ-lyase (CSE), is cardioprotective. Our previous study has shown that estrogens enhance CSE expression in myocardium of female rats. The present study aims to explore the mechanisms by which estrogens regulate CSE expression, in particular to clarify the role of estrogen receptor subtypes and the transcriptional factor responsible for the estrogenic effects. We found that either the CSE inhibitor or the CSE small interfering RNA attenuated the protective effect of 17β-estradiol (E2) against H2O2- and hypoxia/reoxygenation-induced injury in primary cultured neonatal cardiomyocytes. E2 stimulates CSE expression via estrogen receptor (ER)-α both in cultured cardiomyocytes in vitro and in the myocardium of female mice in vivo. A specificity protein-1 (Sp-1) consensus site was identified in the rat CSE promoter and was found to mediate the E2-induced CSE expression. E2 increases ERα and Sp-1 and inhibits microRNA (miR)-22 expression in myocardium of ovariectomized rats. In primary cardiomyocytes, E2 stimulates Sp-1 expression through the ERα-mediated down-regulation of miR-22. It was confirmed that both ERα and Sp-1 were targeted by miR-22. In the myocardium of ovariectomized rats, the level of miR-22 inversely correlated to CSE, ERα, Sp-1, and antioxidant biomarkers and positively correlated to oxidative biomarkers. In summary, this study demonstrates that estrogens stimulate Sp-1 through the ERα-mediated down-regulation of miR-22 in cardiomyocytes, leading to the up-regulation of CSE, which in turn results in an increase of antioxidative defense. Interaction of ERα, miR-22, and Sp-1 may play a critical role in the control of oxidative stress status in the myocardium of female rats.