title: MiR-22/Sp-1 Links Estrogens With the Up-Regulation of Cystathionine γ-Lyase in Myocardium, Which Contributes to Estrogenic Cardioprotection Against Oxidative Stress.
abstract: 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.
authors.affiliation: Department of Physiology and The Key Laboratory of Molecular Neurobiology of the Ministry of Education (L.W., W.Z., B.-H.C., X.-L.T., X.-H.L., X.-Y.Z., X.N.), Second Military Medical University, and School of Kinesiology (Z.-P.T., J.-Q.L.), Key laboratory of Exercise and Health Science of the Ministry of Education, Shanghai University of Sport, Shanghai 200433, China.
authors.forename: Long
authors.initials: L
authors.lastname: Wang
authors.forename: Zhi-Ping
authors.initials: ZP
authors.lastname: Tang
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: Bing-Hai
authors.initials: BH
authors.lastname: Cong
authors.forename: Jian-Qiang
authors.initials: JQ
authors.lastname: Lu
authors.forename: Xiao-Lu
authors.initials: XL
authors.lastname: Tang
authors.forename: Xiao-Han
authors.initials: XH
authors.lastname: Li
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Zhu
authors.forename: Xin
authors.initials: X
authors.lastname: Ni
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003542:Cystathionine gamma-Lyase / Q000235:genetics / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D016329:Sp1 Transcription Factor / Q000378:metabolism*
chemical_list: D004967:Estrogens; C580892:MIRN22 microRNA, rat; D035683:MicroRNAs; C574876:Mirn22 microRNA, mouse; D016329:Sp1 Transcription Factor; D004958:Estradiol; D003542:Cystathionine gamma-Lyase