Context: 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.
Methods And 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).
Conclusion: In conclusion, dietarily relevant levels of resveratrol abrogate the antimitogenic effects of estradiol by inhibiting CYP450-mediated estradiol metabolism and blocking estrogen receptor-alpha.
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| http://dx.doi.org/10.1210/jc.2010-0460 | DOI Listing |
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