Estrogen stimulates dimethylarginine dimethylaminohydrolase activity and the metabolism of asymmetric dimethylarginine
Estrogen stimulates dimethylarginine dimethylaminohydrolase activity and the metabolism of asymmetric dimethylarginine
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DOI：
10.1161/01.cir.0000091083.61609.df
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发表时间：
2003-09-30
期刊：
影响因子：
37.8
通讯作者：
Whitley, GS
中科院分区：
文献类型：
--
作者：
Holden, DP;Cartwright, JE;Whitley, GS
背景-实验证据表明雌激素刺激血管内皮细胞产生一氧化氮（NO）.这种效应归因于NO合酶的组成型和诱导型亚型的表达和酶活性增加。在这项研究中，我们已经调查了雌激素是否调节代谢或释放的不对称二甲基精氨酸（ADMA），内源性抑制剂NO synthes.Methods和结果-ADMA的浓度在血浆中的15绝经后妇女为0.722 +/- 0.04 μ mol/L（平均值+/- SEM）。皮下植入雌二醇两周后，血浆雌二醇浓度从0.693 +/- 0.075增加至0.81 +/- 87 nmol/L，同时血浆ADMA浓度显著下降至0.588 +/- 0.03 mumol/L（P = 0.006）。人和小鼠内皮细胞系先前培养在无雌激素的培养基中，然后暴露于17 β-雌二醇显示ADMA的释放呈剂量依赖性减少。这在10（-14）mol/L 17 β-雌二醇时达到统计学显著性，并伴随着二甲基精氨酸二甲氨基水解酶（DDAH）活性的相应增加，DDAH是一种催化ADMA代谢的酶。结论-我们已经证明雌激素可以改变体外ADMA的催化和释放，并降低体内循环浓度。因此，我们建议DDAH活性增加和随后的ADMA下降可能有助于雌激素对NO合成的积极影响。
Background - Experimental evidence suggests that estrogens stimulate the production of nitric oxide ( NO) by vascular endothelial cells. This effect has been attributed to increased expression and enzymatic activity of both the constitutive and inducible isoforms of NO synthase. In this study, we have investigated whether estrogens regulate the metabolism or release of asymmetric dimethylarginine ( ADMA), an endogenous inhibitor of NO synthase.Methods and Results - The concentration of ADMA in the plasma of 15 postmenopausal women was 0.722 +/- 0.04 mumol/L (mean +/- SEM). Two weeks after subcutaneous implantation with estradiol, there was an increase in plasma estradiol concentration from 0.693 +/- 0.075 to 0.81 +/- 87 nmol/L, which was accompanied by a significant fall in plasma ADMA concentration to 0.588 +/- 0.03 mumol/L (P = 0.006). Human and murine endothelial cell lines previously cultured in estrogen-free medium and then exposed to 17beta-estradiol showed a dose-dependent decrease in the release of ADMA. This reached statistical significance at 10(-14) mol/L 17beta-estradiol and was accompanied by a corresponding increase in the activity of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme that catalyzes the metabolism of ADMA.Conclusions - We have demonstrated that estrogens can alter the catabolism and release of ADMA in vitro and reduce the circulating concentration in vivo. We therefore propose that increased DDAH activity and the subsequent fall in ADMA could contribute to the positive effect of estrogen on NO synthesis.