27-Hydroxycholesterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen.
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.
Umetani
Michihisa
M
Department of Pharmacology and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, Texas 75390-9050, USA.
Domoto
Hideharu
H
Gormley
Andrew K
AK
Yuhanna
Ivan S
IS
Cummins
Carolyn L
CL
Javitt
Norman B
NB
Korach
Kenneth S
KS
Shaul
Philip W
PW
Mangelsdorf
David J
DJ
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D002316:Cardiotonic Agents / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology*; D018929:Cell Culture Techniques; D002460:Cell Line; D002478:Cells, Cultured; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D018076:DNA, Complementary; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D006888:Hydroxycholesterols / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007279:Injections, Subcutaneous; D007668:Kidney / Q000166:cytology; D007700:Kinetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D012333:RNA, Messenger / Q000378:metabolism; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects
D002316:Cardiotonic Agents; D002791:Cholesterol, Dietary; D018076:DNA, Complementary; D004967:Estrogens; D006888:Hydroxycholesterols; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D020845:Selective Estrogen Receptor Modulators; D009569:Nitric Oxide; C076996:27-hydroxycholesterol; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; D005982:Glutathione Transferase