STKE: An Endogenous SERM?

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Science  26 Oct 2007:
Vol. 318, Issue 5850, pp. 537c
DOI: 10.1126/science.318.5850.537c

Although estrogens had long been thought to protect against cardiovascular disease, this assumption has been challenged by the results of clinical trials that failed to corroborate protective effects of hormone replacement therapy in postmenopausal women. Umetani et al. found that the cholesterol metabolite 27-hydroxycholesterol (27HC, which is found in atherosclerotic lesions) competed with estradiol for binding to estrogen receptors α and β (ERα and ERβ), inhibited estradiol-dependent activation of transcriptional activity of the receptors, and inhibited the estradiol-dependent association of ERβ with the transcriptional coactivator SRC-1. In mice fed a diet rich in cholesterol and fat, hypercholesterolemia was associated with increased vascular concentrations of 27HC, comparable to those affecting ER function; 27HC also inhibited the estradiol-dependent increase in inducible and endothelial nitric oxide synthase (iNOS and eNOS) expression in mouse aortic cultures. Administration of 27HC decreased aortic expression of iNOS and eNOS in vivo, and dietary hypercholesterolemia was associated with a decrease in iNOS mRNA and protein in male mice. The pro- or anti-estrogenic effects of 27HC depended on tissue type, leading the authors to propose that it may act as an endogenous selective estrogen response modulator (SERM). The anti-estrogenic effects of 27HC in the vasculature led them to suggest that it might contribute to a lack of cardioprotective effects of estrogen in postmenopausal women. — EMA

Nat. Med. 13, 1185 (2007).

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