(Hypertension. 2001;37:658.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Increased 2-Methoxyestradiol Production in Human Coronary Versus Aortic Vascular Cells
From the Center for Clinical Pharmacology (L.C.Z., E.K.J., D.G.G., R.K.D.), Departments of Medicine (E.K.J., D.G.G., R.K.D.) and Pharmacology (L.C.Z., E.K.J.), University of Pittsburgh Medical Center, Pittsburgh, Pa; the Clinic for Endocrinology (R.K.D.) Department of Obstetrics and Gynecology, University Hospital Zurich (Switzerland).
Correspondence to Dr Raghvendra K. Dubey, D217, NORD-1, Clinic for Endocrinology, Department of Obstetrics and Gynecology, Frauenklinik Zurich 8091, Switzerland. E-mail rag{at}fhk.usz.ch
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 Vmax, Km, and Vmax/Km ratio values for conversion of 2-hydroxyestradiol to 2-methoxyestradiol were 19±0.69 pmol · min-1 per 106 cells, 0.52±0.085 µmol/L, and 44±4.9 pmol · min-1 · µmol/L per 106 cells, respectively. In human coronary artery vascular smooth muscle cells, the Vmax, Km, and Vmax/Km ratio values for conversion of 2-hydroxyestradiol to 2-methoxyestradiol were 16±0.59 pmol · min-1 per 106 cells, 0.23±0.011 µmol/L, and 69±3.6 pmol · min-1 · µmol/L per 106 cells, respectively (all values significantly different compared with human aortic smooth muscle cells). Also, in human aortic versus coronary artery endothelial cells, the Vmax (33±0.24 versus 22±0.33 pmol · min-1 per 106 cells, respectively), Km (0.20±0.010 versus 0.099±0.014 µmol/L, respectively), and Vmax/Km (163±7.7 versus 243±41 pmol · min-1 · µmol/L per 106 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 Km and higher Vmax/Km 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.
Key Words: catechol-O-methyltransferase • estrogen • endothelium • muscle, smooth, vascular • coronary artery disease
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