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(Circulation. 2009;120:245-254.)
© 2009 American Heart Association, Inc.

Molecular Cardiology

Estrogen Receptor-β Activation Results in S-Nitrosylation of Proteins Involved in Cardioprotection

Jeffrey Lin, MD; Charles Steenbergen, MD, PhD; Elizabeth Murphy, PhD; Junhui Sun, PhD

From Harvard Medical School, Boston, Mass (J.L.); Department of Pathology, Johns Hopkins University, Baltimore, Md (C.S.); and Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md (E.M., J.S.).

Correspondence to Dr Junhui Sun, Translational Medicine Branch, National Heart Lung and Blood Institute, National Institutes of Health, 10 Center Drive, Bldg10, Room 7N111, Bethesda, MD 20892. E-mail sun1{at}mail.nih.gov

Received July 3, 2008; accepted April 27, 2009.

Background— It has been shown that the activation of estrogen receptor-β (ER-β) 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-β activation, which leads to S-nitrosylation (SNO) of key cardioprotective proteins.

Methods and Results— We treated ovariectomized C57BL/6J mice with the ER-β selective agonist 2,2-bis(4-hydroxyphenyl)-proprionitrile (DPN), 17β-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-β–knockout mice with DPN. However, no cardioprotective effect of DPN was found in ER-β–knockout mice, indicating that the DPN-induced cardioprotection occurs through the activation of ER-β. 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.

Conclusion— The activation of ER-β 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-β and nitric oxide/SNO signaling.

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CLINICAL PERSPECTIVE

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Assays for S-Nitrosothiols and S-Nitrosylated Proteins and Mechanistic Insights Into Cardioprotection

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Circulation 2009 120: 190-193. [Extract] [Full Text]

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				D. T. Hess, M. W. Foster, and J. S. Stamler Assays for S-Nitrosothiols and S-Nitrosylated Proteins and Mechanistic Insights Into Cardioprotection Circulation, July 21, 2009; 120(3): 190 - 193. [Full Text] [PDF]