An Endogenous SERM?

Science's STKE  16 Oct 2007:
Vol. 2007, Issue 408, pp. tw373
DOI: 10.1126/stke.4082007tw373

Although estrogens have long been thought to be protective against cardiovascular disease, this assumption has been challenged by clinical trials that failed to corroborate such 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 receptor 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 diets rich in cholesterol and fat, hypercholesterolemia was associated with increased vascular concentrations of 27HC, so that it reached concentrations comparable to those affecting ER function. 27HC inhibited the estradiol-dependent increase in mRNA encoding inducible and endothelial nitric oxide synthase (iNOS and eNOS) in mouse aortic cultures, as well as estradiol-dependent NOS activity in rat aortic rings and lysates of a vascular smooth muscle cell line. Furthermore, 27HC reversed the estradiol-dependent inhibition of phenylephrine-mediated constriction of rat aortic rings. 27HC administration also decreased aortic expression of the mRNA encoding iNOS and eNOS in vivo, and dietary hypercholesterolemia was associated with a decrease in iNOS mRNA and protein in male mice. 27HC inhibited the rapid (nontranscriptional) estradiol-dependent stimulation of eNOS activity in bovine aortic endothelial cells, as well as estradiol-dependent endothelial cell migration in vitro and re-endothelialization in vivo. The pro- or anti-estrogenic effects of 27HC depended on tissue type, leading the authors to propose that it acted as an endogenous selective estrogen receptor 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.

M. Umetani, H. Domoto, A. K. Gormley, I. S. Yuhanna, C. L. Cummins, N. B. Javitt, K. S. Korach, P. W. Shaul, D. J. Mangelsdorf, 27-Hydroxycholesterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen. Nat. Med. 13, 1185-1192 (2007). [PubMed]