Article abstract
Nature Medicine 13, 1185 - 1192 (2007)
Published online: 16 September 2007 | doi:10.1038/nm1641
27-Hydroxycholesterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen
Michihisa Umetani1, Hideharu Domoto1, Andrew K Gormley2, Ivan S Yuhanna2, Carolyn L Cummins1, Norman B Javitt3, Kenneth S Korach4, Philip W Shaul2 & David J Mangelsdorf1
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.
- Department of Pharmacology and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, Texas 75390-9050, USA.
- Department of Pediatrics, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, Texas 75390-9050, USA.
- Department of Pediatrics and Medicine, New York University School of Medicine, New York, New York 10016, USA.
- 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.
Correspondence to: David J Mangelsdorf1 e-mail: davo.mango@utsouthwestern.edu
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