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27-Hydroxycholesterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen

Abstract

The cardioprotective effects of estrogen are mediated by receptors expressed in vascular cells. Here we show that 27-hydroxycholesterol (27HC), an abundant cholesterol metabolite that is elevated with hypercholesterolemia and found in atherosclerotic lesions, is a competitive antagonist of estrogen receptor action in the vasculature. 27HC inhibited both the transcription-mediated and the non-transcription-mediated estrogen-dependent production of nitric oxide by vascular cells, resulting in reduced estrogen-induced vasorelaxation of rat aorta. Furthermore, increasing 27HC levels in mice by diet-induced hypercholesterolemia, pharmacologic administration or genetic manipulation (by knocking out the gene encoding the catabolic enzyme CYP7B1) decreased estrogen-dependent expression of vascular nitric oxide synthase and repressed carotid artery reendothelialization. As well as antiestrogenic effects, there were proestrogenic actions of 27HC that were cell-type specific, indicating that 27HC functions as an endogenous selective estrogen receptor modulator (SERM). Taken together, these studies point to 27HC as a contributing factor in the loss of estrogen protection from vascular disease.

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Figure 1: 27HC inhibition of estrogen receptors.
Figure 2: 27HC inhibits the actions of E2 on NO production in vascular cells.
Figure 3: 27HC decreases vascular NOS expression in an ER-dependent manner.
Figure 4: 27HC Inhibits nontranscriptional effects of E2 on NOS enzyme activity in vascular cells.
Figure 5: 27HC inhibits E2-induced endothelial cell migration and reendothelialization in mice.
Figure 6: Model of 27HC inhibition of the vasoprotective effects of estrogen.

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Acknowledgements

The authors thank Y. Mizuno, K. Kamm, J. Stull and D. Seetharam for help with NOS activity, aortic tension measurement and cell migration assays; C.J.S. Edgell (University of North Carolina) for providing EA.hy926 cells; A. Liverman (University of Texas Southwestern) for aorta samples; D.W. Russell (University of Texas Southwestern) for Cyp7b1−/− mice; and S. Kliewer and members of the Mangelsdorf lab for discussions and suggestions. D.J.M. is an investigator at the Howard Hughes Medical Institute. This work was funded by the Howard Hughes Medical Institute, the Robert A. Welch Foundation (grant I-1275), and US National Institutes of Health grants HL87564 (P.W.S., D.J.M.) and U19DK62434 (D.J.M.).

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M.U. designed, executed and interpreted most of the experiments and prepared the manuscript. H.D. performed initial experiments showing that 27HC is an ER ligand. A.K.G. performed reendothelialization experiments. I.S.Y. performed NOS enzyme assays. C.L.C. designed and performed the LC/MS experiments. N.B.J. synthesized and formulated 27HC. K.S.K. supplied the Esr−/− mice and contributed to the design of the mouse studies. P.W.S. and D.J.M. conceived, planned and supervised the project and wrote the paper.

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Correspondence to David J Mangelsdorf.

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Umetani, M., Domoto, H., Gormley, A. et al. 27-Hydroxycholesterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen. Nat Med 13, 1185–1192 (2007). https://doi.org/10.1038/nm1641

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