Journal Article

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

Javitt, Norman B, Shaul, Philip W, Mangelsdorf, David J, Korach, Kenneth S, Domoto, Hideharu, Yuhanna, Ivan S, Umetani, Michihisa, Gormley, Andrew K, Cummins, Carolyn L

2007

Overview

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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Animals / Aorta, Thoracic - drug effects / Binding, Competitive - drug effects / Biochemistry / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cardiotonic Agents - antagonists & inhibitors / Cardiotonic Agents - metabolism / Cardiotonic Agents - pharmacology / Cardiovascular disease / Cell Culture Techniques / Cell Line / Cells, Cultured / Cellular biology / Cholesterol / Cholesterol, Dietary - administration & dosage / DNA, Complementary / Dose-Response Relationship, Drug / Drug Administration Schedule / Estrogens / Estrogens - metabolism / Estrogens - pharmacology / Female / Glutathione Transferase - metabolism / Humans / Hydroxycholesterols - administration & dosage / Hydroxycholesterols - blood / Hydroxycholesterols - pharmacology / Infectious Diseases / Inhibitory Concentration 50 / Injections, Subcutaneous / Kidney - cytology / Kinetics / Lesions / Male / Medical research / Metabolic Diseases / Metabolites / Mice / Mice, Knockout / Molecular Medicine / Neurosciences / Nitric oxide / Nitric Oxide - antagonists & inhibitors / Nitric Oxide Synthase Type II - antagonists & inhibitors / Nitric Oxide Synthase Type III / Receptors, Estrogen - antagonists & inhibitors / Receptors, Estrogen - genetics / Recombinant Fusion Proteins - antagonists & inhibitors / RNA, Messenger - metabolism / Rodents / Selective Estrogen Receptor Modulators - administration & dosage / Selective Estrogen Receptor Modulators - blood / Selective Estrogen Receptor Modulators - pharmacology / Vascular diseases / Vasodilation - drug effects