Resveratrol, a red wine constituent, blocks the antimitogenic effects of estradiol on human female coronary artery smooth muscle cells.
BACKGROUND
Antimitogenic effects of estradiol on vascular smooth muscle cells (VSMCs) may be cardioprotective, and these effects are mediated by estrogen receptor-alpha-dependent and -independent mechanisms, with the latter involving the conversion of estradiol to 2-hydroxyestradiol/2-methoxyestradiol by CYP450. Because resveratrol inhibits CYP450 and is an estrogen-receptor-alpha antagonist, resveratrol may abrogate the antimitogenic effects of estradiol.


OBJECTIVE
The objective of the study was to examine the interaction of pharmacologically relevant concentrations of resveratrol with estradiol, 2-hydroxyestradiol, and 2-methoxyestradiol in human female coronary artery VSMCs.


RESULTS
In human female coronary VSMCs, resveratrol (0.1-10 microm) alone did not influence serum-induced DNA or collagen synthesis or cell proliferation or migration; however, resveratrol abrogated the inhibitory effects of estradiol, but not 2-hydroxyestradiol or 2-methoxyestradiol, on these responses. Resveratrol also abrogated the inhibitory effects of estradiol on positive growth regulators (cyclin A, cyclin D, MAPK phosphorylation) and the stimulatory effects of estradiol on negative growth regulators (p21, p27). In microsomes and cells, dietarily relevant levels of resveratrol (0.001-1 microm) inhibited the metabolism of estradiol to 2-hydroxestradiol/2-methoxyestradiol. Propylpyrazoletriol (estrogen receptor-alpha agonist, 100 nmol/liter), but not diarylpropionitrile (estrogen receptor-beta agonist, 10 nmol/liter), inhibited VSMC mitogenesis, and this effect was blocked by resveratrol (5 micromol/liter). Higher concentrations (>25-50 microm) of resveratrol, never attainable in vivo, inhibited VSMC growth, an effect blocked by GW9662 (peroxisomal proliferator-activated receptor-gamma antagonist).


CONCLUSIONS
In conclusion, dietarily relevant levels of resveratrol abrogate the antimitogenic effects of estradiol by inhibiting CYP450-mediated estradiol metabolism and blocking estrogen receptor-alpha.
Department of Obstetrics and Gynecology, Clinic for Reproductive Endocrinology, University Hospital Zurich, Zurich 8091-CH, Switzerland. raghvendra.dubey@usz.ch
Raghvendra K
RK
Dubey
Edwin K
EK
Jackson
Delbert G
DG
Gillespie
Lefteris C
LC
Zacharia
Bruno
B
Imthurn
Marinella
M
Rosselli
D050256:Antimitotic Agents / Q000037:antagonists & inhibitors; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009994:Osmolar Concentration; D000077185:Resveratrol; D012737:Sex Factors; D013267:Stilbenes / Q000494:pharmacology*; D027843:Vitis / Q000737:chemistry; D014920:Wine
D050256:Antimitotic Agents; D006727:Hormone Antagonists; D013267:Stilbenes; D004958:Estradiol; D000077185:Resveratrol