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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Aorta, Thoracic / drug effects
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Binding, Competitive / drug effects
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Cardiotonic Agents / antagonists & inhibitors*
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Cardiotonic Agents / metabolism
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Cardiotonic Agents / pharmacology*
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Cell Culture Techniques
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Cell Line
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Cells, Cultured
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Cholesterol, Dietary / administration & dosage
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DNA, Complementary
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Dose-Response Relationship, Drug
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Drug Administration Schedule
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Estrogens / metabolism
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Estrogens / pharmacology*
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Female
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Glutathione Transferase / metabolism
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Humans
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Hydroxycholesterols / administration & dosage
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Hydroxycholesterols / blood
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Hydroxycholesterols / pharmacology*
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Inhibitory Concentration 50
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Injections, Subcutaneous
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Kidney / cytology
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Kinetics
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Male
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Mice
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Mice, Knockout
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Nitric Oxide / antagonists & inhibitors
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Nitric Oxide Synthase Type II / antagonists & inhibitors
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Nitric Oxide Synthase Type III
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RNA, Messenger / metabolism
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Receptors, Estrogen / antagonists & inhibitors
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Receptors, Estrogen / genetics
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Recombinant Fusion Proteins / antagonists & inhibitors
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Selective Estrogen Receptor Modulators / administration & dosage
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Selective Estrogen Receptor Modulators / blood
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Selective Estrogen Receptor Modulators / pharmacology*
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Vasodilation / drug effects
Substances
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Cardiotonic Agents
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Cholesterol, Dietary
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DNA, Complementary
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Estrogens
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Hydroxycholesterols
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RNA, Messenger
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Receptors, Estrogen
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Recombinant Fusion Proteins
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Selective Estrogen Receptor Modulators
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Nitric Oxide
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27-hydroxycholesterol
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Nitric Oxide Synthase Type II
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Nitric Oxide Synthase Type III
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Nos2 protein, mouse
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Nos3 protein, mouse
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Glutathione Transferase