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Estrogen receptor-beta activation results in S-nitrosylation of proteins involved in cardioprotection.

ABSTRACT: BACKGROUND:It has been shown that the activation of estrogen receptor-beta (ER-beta) plays an important cardioprotective role against ischemia/reperfusion injury. However, the mechanism for this protection is not clear. We hypothesize that estrogen protects by ER-beta activation, which leads to S-nitrosylation (SNO) of key cardioprotective proteins. METHODS AND RESULTS:We treated ovariectomized C57BL/6J mice with the ER-beta selective agonist 2,2-bis(4-hydroxyphenyl)-proprionitrile (DPN), 17beta-estradiol (E2), or vehicle using Alzet minipumps for 2 weeks. Isolated hearts were Langendorff perfused and subjected to ischemia and reperfusion. Compared with vehicle-treated hearts, DPN- and E2-treated hearts had significantly better postischemic functional recovery and decreased infarct size. To test the specificity of DPN, we treated ER-beta-knockout mice with DPN. However, no cardioprotective effect of DPN was found in ER-beta-knockout mice, indicating that the DPN-induced cardioprotection occurs through the activation of ER-beta. Using DyLight-maleimide fluors and a modified biotin switch method, we used a 2-dimensional DyLight fluorescence difference gel electrophoresis proteomic method to quantify differences in SNO of proteins. DPN- and E2-treated hearts showed an increase in SNO of a number of proteins. Interestingly, many of these proteins also had been shown to have increased SNO in preconditioned hearts. In addition, the DPN-induced cardioprotection and increased SNO were abolished by treatment with a nitric oxide synthase inhibitor. CONCLUSIONS:The activation of ER-beta by DPN treatment leads to increased protein SNO and cardioprotection against ischemia/reperfusion injury, suggesting that long-term estrogen exposure protects hearts largely via activation of ER-beta and nitric oxide/SNO signaling.

SUBMITTER: Lin J

PROVIDER: S-EPMC2778304 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Estrogen receptor-beta activation results in S-nitrosylation of proteins involved in cardioprotection.

Lin Jeffrey J Steenbergen Charles C Murphy Elizabeth E Sun Junhui J

Circulation 20090706 3

<h4>Background</h4>It has been shown that the activation of estrogen receptor-beta (ER-beta) plays an important cardioprotective role against ischemia/reperfusion injury. However, the mechanism for this protection is not clear. We hypothesize that estrogen protects by ER-beta activation, which leads to S-nitrosylation (SNO) of key cardioprotective proteins.<h4>Methods and results</h4>We treated ovariectomized C57BL/6J mice with the ER-beta selective agonist 2,2-bis(4-hydroxyphenyl)-proprionitril ...[more]

PMID: 19581491

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Project description:Recent researches have shown that estrogen receptor-β (ERβ) activator may be a potent anticancer agent for prostate cancer (PCa), and our previous study also indicated that dioscin can upregulate the expression of ERβ in MC3T3-E1 cell. In the present work, the activity and mechanism of dioscin, a natural product, against PCa were investigated. The results showed that dioscin markedly inhibited cell viability, colony formation, motility and induced apoptosis in PC3 cells. Moreover, dioscin disrupted the formation of PC3 cell-derived mammospheres and reduced aldehyde dehydrogenase (ALDH) level and the CD133+/CD44+ cells, indicating that dioscin had a potent inhibitory activity on prostate cancer stem cells (PCSCs). In vivo results also showed that dioscin significantly suppressed the tumor growth of PC3 cell xenografts in nude mice. Furthermore, mechanism investigation showed that dioscin markedly upregulated ERβ expression level, subsequently increased prolyl hydroxylase 2 level, decreased the levels of hypoxia-inducible factor-1α, vascular endothelial growth factor A and BMI-1, and thus induced cell apoptosis by regulating the expression levels of caspase-3 and Bcl-2 family proteins. In addition, transfection experiment of ERβ-siRNA further indicated that diosicn showed excellent activity against PCa in vitro and in vivo by increasing ERβ expression level. The co-immunoprecipitation (Co-IP) results further suggested that dioscin promoted the interaction of c-ABL and ERβ, but did not change c-ABL expression. Moreover, the molecular docking assay showed that dioscin processed powerful affinity toward to ERβ mainly through the strong hydrogen bonding and hydrophobic effects, and the actions of dioscin on ERβ activation and tumor cells inhibition were significantly weakened in the mutational (Phe-336, Phe-468) PC3 cells. Collectively, these findings proved that dioscin exerted efficient anti-PCa activity via activation of ERβ, which should be developed as an efficient candidate in clinical for treating this cancer in the future.

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Estrogen receptor-beta activation results in S-nitrosylation of proteins involved in cardioprotection.

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Estrogen receptor-beta activation results in S-nitrosylation of proteins involved in cardioprotection.

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