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

Nature Medicine volume 13, pages 11851192 (2007) | Download Citation

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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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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.).

Author information

Affiliations

  1. Department of Pharmacology and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, Texas 75390-9050, USA.

    • Michihisa Umetani
    • , Hideharu Domoto
    • , Carolyn L Cummins
    •  & David J Mangelsdorf
  2. Department of Pediatrics, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, Texas 75390-9050, USA.

    • Andrew K Gormley
    • , Ivan S Yuhanna
    •  & Philip W Shaul
  3. Department of Pediatrics and Medicine, New York University School of Medicine, New York, New York 10016, USA.

    • Norman B Javitt
  4. Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, PO Box 12233, 111 Alexander Drive, Research Triangle Park, North Carolina 27709, USA.

    • Kenneth S Korach

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Contributions

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.

Corresponding author

Correspondence to David J Mangelsdorf.

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DOI

https://doi.org/10.1038/nm1641

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