Zerr-Fouineau Murielle, Jourdain Marie, Boesch Caroline, Hecker Markus, Bronner Christian, Schini-Kerth Valérie B
Département de Pharmacologie et Physico-Chimie, Institut Gilbert Laustriat, Université Louis Pasteur Strasbourg I, Illkirch, France.
Arterioscler Thromb Vasc Biol. 2009 Apr;29(4):586-93. doi: 10.1161/ATVBAHA.108.178004. Epub 2008 Dec 18.
Estro-progestin treatments have been associated with an increased risk of thromboembolic events in postmenopausal women. This study examined whether progestins affect the stimulatory effect of estrogens on the endothelial formation of nitric oxide (NO), a potent antithrombotic factor.
Experiments were performed with human endothelial cells. Endothelial NO synthase (eNOS) and GTP cyclohydrolase I (GTPCH I) mRNA expression was assessed by RT-PCR, eNOS protein by Western blotting, NO formation by electron spin resonance spectroscopy, and platelet aggregation by an aggregometer. Medroxyprogesterone acetate (MPA), progesterone, levonorgestrel, and nomegestrol acetate prevented the 17beta-estradiol (17beta-E)-induced expression of eNOS mRNA and protein. MPA and progesterone reduced the 17beta-E-induced formation of NO and potentiation of the inhibitory effect of endothelial cells on platelet aggregation whereas levonorgestrel and nomegestrol acetate were without effect. Moreover, MPA and progesterone prevented the 17beta-E-induced expression of GTPCH I mRNA. Mifepristone, a glucocorticoid and progesterone receptor antagonist, and L-sepiapterin prevented the inhibitory effect of MPA and progesterone on platelet aggregation.
Certain progestins, including MPA, attenuate the 17beta-E-induced NO-mediated inhibition of platelet aggregation by endothelial cells through preventing both eNOS and GTPCH I expression most likely via activation of glucocorticoid receptors.
雌激素 - 孕激素治疗与绝经后女性血栓栓塞事件风险增加有关。本研究探讨孕激素是否会影响雌激素对一氧化氮（NO，一种有效的抗血栓因子）内皮生成的刺激作用。
用人内皮细胞进行实验。通过逆转录聚合酶链反应（RT-PCR）评估内皮型一氧化氮合酶（eNOS）和GTP环水解酶I（GTPCH I）mRNA表达，通过蛋白质印迹法检测eNOS蛋白，通过电子自旋共振光谱法检测NO生成，通过血小板聚集仪检测血小板聚集。醋酸甲羟孕酮（MPA）、孕酮、左炔诺孕酮和醋酸诺美孕酮可阻止17β-雌二醇（17β-E）诱导的eNOS mRNA和蛋白表达。MPA和孕酮可降低17β-E诱导的NO生成以及增强内皮细胞对血小板聚集的抑制作用，而左炔诺孕酮和醋酸诺美孕酮则无此作用。此外，MPA和孕酮可阻止17β-E诱导的GTPCH I mRNA表达。米非司酮（一种糖皮质激素和孕酮受体拮抗剂）和L-四氢生物蝶呤可阻止MPA和孕酮对血小板聚集的抑制作用。
某些孕激素，包括MPA，通过最有可能经由糖皮质激素受体激活来阻止eNOS和GTPCH I表达，从而减弱17β-E诱导的内皮细胞通过NO介导的对血小板聚集的抑制作用。
