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J. Biol. Chem., Vol. 281, Issue 37, 27335-27345, September 15, 2006

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The Isoflavone Equol Mediates Rapid Vascular Relaxation

Ca²⁺-INDEPENDENT ACTIVATION OF ENDOTHELIAL NITRIC-OXIDE SYNTHASE/Hsp90 INVOLVING ERK1/2 AND Akt PHOSPHORYLATION IN HUMAN ENDOTHELIAL CELL^*

Sheeja Joy¹², Richard C. M. Siow¹, David J. Rowlands³, Marko Becker, Amanda W. Wyatt⁴, Philip I. Aaronson, Clive W. Coen^¶5, Imre Kallo^¶||5, Ron Jacob, and Giovanni E. Mann⁶

From the Cardiovascular Division, ^¶Reproduction and Endocrinology Division, Asthma, Allergy, and Lung Biology Division, Schools of Biomedical and Health Sciences and Medicine, King's College London, Guy's Campus, London SE1 1UL, United Kingdom and the ^||Laboratory of Endocrine and Behavioural Neurobiology, Institute of Experimental Medicine, Budapest 1083, Hungary

We recently reported that soy isoflavones increase gene expression of endothelial nitric-oxide synthase (eNOS) and antioxidant defense enzymes, resulting in improved endothelial function and lower blood pressure in vivo. In this study, we establish that equol (1-100 nM) causes acute endothelium- and nitric oxide (NO)-dependent relaxation of aortic rings and rapidly (2 min) activates eNOS in human aortic and umbilical vein endothelial cells. Intracellular Ca²⁺ and cyclic AMP levels were unaffected by treatment (100 nM, 2 min) with equol, daidzein, or genistein. Rapid phosphorylation of ERK1/2, protein kinase B/Akt, and eNOS serine 1177 by equol was paralleled by association of eNOS with heat shock protein 90 (Hsp90) and NO synthesis in human umbilical vein endothelial cells, expressing estrogen receptors (ER) and ER. Inhibition of phosphatidylinositol 3-kinase and ERK1/2 inhibited eNOS activity, whereas pertussis toxin and the ER antagonists ICI 182,750 and tamoxifen had negligible effects. Our findings provide the first evidence that nutritionally relevant plasma concentrations of equol (and other soy protein isoflavones) rapidly stimulate phosphorylation of ERK1/2 and phosphatidylinositol 3-kinase/Akt, leading to the activation of NOS and increased NO production at resting cytosolic Ca²⁺ levels. Identification of the nongenomic mechanisms by which equol mediates vascular relaxation provides a basis for evaluating potential benefits of equol in the treatment of postmenopausal women and patients at risk of cardiovascular disease.

Received for publication, March 24, 2006 , and in revised form, May 22, 2006.

^* This work was supported in part by British Heart Foundation Grant FS/99075, Biotechnology and Biological Sciences Research Council Grant BBS/S/K/2004/11207, Medical Research Council Grant G78/5887, and Heart Research UK Grant RG22489/04/08. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² Recipient of a British Heart Foundation studentship.

³ Recipient of a Biotechnology and Biological Sciences Research Council studentship.

⁴ Recipient of a Medical Research Council studentship.

⁵ Recipient of Wellcome Trust Grant 060202.

⁶ To whom correspondence should be addressed. Tel.: 44-20-7848-6209; Fax: 44-20-7848-6220; E-mail: giovanni.mann{at}kcl.ac.uk.

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