Zacharia L C, Jackson E K, Gillespie D G, Dubey R K
Center for Clinical Pharmacology, Departments of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Hypertension. 2001 Feb;37(2 Pt 2):658-62. doi: 10.1161/01.hyp.37.2.658.
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.
雌二醇可能具有心脏保护作用；然而，其中涉及的机制仍不清楚。最近有研究发现，雌二醇可减轻雌激素受体基因敲除小鼠的新生内膜形成，这表明雌二醇的心脏保护作用可能通过不依赖雌激素受体的机制介导。由于2-甲氧基雌二醇是雌二醇的一种内源性代谢产物，对雌激素受体无亲和力，但其在抑制血管平滑肌细胞生长方面比雌二醇更有效，因此2-甲氧基雌二醇可能部分介导了雌二醇的心脏保护作用。为验证这一假说，我们研究了血管平滑肌细胞和内皮细胞中2-甲氧基雌二醇的合成动力学。在人主动脉平滑肌细胞中，2-羟基雌二醇转化为2-甲氧基雌二醇的V(max)、K(m)和V(max)/K(m)比值分别为19±0.69 pmol·min⁻¹/10⁶细胞、0.52±0.085 μmol/L和44±4.9 pmol·min⁻¹·μmol/L/10⁶细胞。在人冠状动脉血管平滑肌细胞中，2-羟基雌二醇转化为2-甲氧基雌二醇的V(max)、K(m)和V(max)/K(m)比值分别为16±0.59 pmol·min⁻¹/10⁶细胞、0.23±0.011 μmol/L和69±3.6 pmol·min⁻¹·μmol/L/10⁶细胞（所有数值与人主动脉平滑肌细胞相比均有显著差异）。此外，在人主动脉与冠状动脉内皮细胞中，V(max)（分别为33±0.24与22±0.33 pmol·min⁻¹/10⁶细胞）、K(m)（分别为0.20±0.010与0.099±0.014 μmol/L）和V(max)/K(m)（分别为163±7.7与243±41 pmol·min⁻¹·μmol/L/10⁶细胞）数值也有显著差异。我们的结果表明，血管平滑肌细胞和内皮细胞可有效地将2-羟基雌二醇代谢为2-甲氧基雌二醇。人冠状动脉细胞较低的K(m)和较高的V(max)/K(m)比值表明，在2-羟基雌二醇水平较低时，冠状动脉循环中2-羟基雌二醇向2-甲氧基雌二醇的局部代谢速率更快。
