Increased 2-methoxyestradiol production in human coronary versus aortic vascular cells.
Estradiol may be cardioprotective; however, the mechanisms involved remain unclear. Recent findings that estradiol attenuates neointima formation in estrogen receptor knockout mice suggest that the cardioprotective effects of estradiol may be mediated through estrogen receptor-independent mechanisms. Because 2-methoxyestradiol, an endogenous metabolite of estradiol with no affinity for estrogen receptors, is more potent than estradiol in inhibiting vascular smooth muscle cell growth, it is feasible that 2-methoxyestradiol mediates in part the cardioprotective effects of estradiol. To address this hypothesis, we examined the kinetics of 2-methoxyestradiol synthesis in vascular smooth muscle cells and endothelial cells. In human aortic smooth muscle cells, the V(max), K(m), and V(max)/K(m) ratio values for conversion of 2-hydroxyestradiol to 2-methoxyestradiol were 19+/-0.69 pmol. min(-1) per 10(6) cells, 0.52+/-0.085 micromol/L, and 44+/-4.9 pmol. min(-1). micromol/L per 10(6) cells, respectively. In human coronary artery vascular smooth muscle cells, the V(max), K(m), and V(max)/K(m) ratio values for conversion of 2-hydroxyestradiol to 2-methoxyestradiol were 16+/-0.59 pmol. min(-1) per 10(6) cells, 0.23+/-0.011 micromol/L, and 69+/-3.6 pmol. min(-1). micromol/L per 10(6) cells, respectively (all values significantly different compared with human aortic smooth muscle cells). Also, in human aortic versus coronary artery endothelial cells, the V(max) (33+/-0.24 versus 22+/-0.33 pmol. min(-1) per 10(6) cells, respectively), K(m) (0.20+/-0.010 versus 0.099+/-0.014 micromol/L, respectively), and V(max)/K:(m) (163+/-7.7 versus 243+/-41 pmol. min(-1). micromol/L per 10(6) cells, respectively) values were significantly different. Our results indicate that vascular smooth muscle and endothelial cells effectively metabolize 2-hydroxyestradiol to 2-methoxyestradiol. The lower K(m) and higher V(max)/K(m) ratio of human coronary versus aortic cells indicate a faster rate of local metabolism of 2-hydroxyestradiol to 2-methoxyestradiol in the coronary circulation at low levels of 2-hydroxyestradiol.
Zacharia
L C
LC
Center for Clinical Pharmacology, Departments of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Jackson
E K
EK
Gillespie
D G
DG
Dubey
R K
RK
D000077584:2-Methoxyestradiol; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D004837:Epinephrine / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000096:biosynthesis* / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D008780:Methyltransferases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D004958:Estradiol; D000077584:2-Methoxyestradiol; C001390:2-hydroxyestradiol; D008780:Methyltransferases; C019608:caffeate O-methyltransferase; D007545:Isoproterenol; D009638:Norepinephrine; D004837:Epinephrine