Sex steroids used in hormonal treatment increase vascular procoagulant activity by inducing thrombin receptor (PAR-1) expression - Role of the glucocorticoid receptor
Sex steroids used in hormonal treatment increase vascular procoagulant activity by inducing thrombin receptor (PAR-1) expression - Role of the glucocorticoid receptor
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DOI：
10.1161/hc4801.099737
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发表时间：
2001-12-04
期刊：
影响因子：
37.8
通讯作者：
Schini-Kerth, VB
中科院分区：
文献类型：
--
作者：
Herkert, O;Kuhl, H;Schini-Kerth, VB
背景：在口服避孕药或激素替代治疗中使用性类固醇与心血管血栓栓塞并发症的风险增加有关。虽然雌激素和黄体酮成分都参与其中，但其潜在机制尚不清楚。方法与结果：本研究考察性类固醇是否通过增加血管促凝活性间接促进止血。用几种黄体酮（孕酮、3-酮-去氧孕酮、孕酮和醋酸甲羟孕酮）处理血管平滑肌细胞可上调蛋白水解活化凝血酶受体（PAR-1）的表达，导致凝血酶诱导的组织因子表达和表面促凝活性增强。相比之下，孕激素左炔诺孕酮、去甲睾酮和诺格估计以及合成雌激素17 α -炔雌醇都没有这种效果。地塞米松可以模拟刺激黄体酮和糖皮质激素受体拮抗剂RU-38486的作用，刺激黄体酮可在多种细胞系统中诱导糖皮质激素样作用。此外，对去卵巢大鼠长期给予黄体酮、3-酮-去孕酮或醋酸甲孕酮可增加动脉壁PAR-1蛋白水平，导致离体主动脉环对凝血酶的反应性增加。结论：这些数据表明，几种孕激素通过增加平滑肌中膜凝血酶受体的可用性，显著增强凝血酶的血管促凝作用，这种作用很可能是由于它们的糖皮质激素样活性。
Background-The use of sex steroids in oral contraception or hormonal replacement therapy is associated with an increased risk of cardiovascular thromboembolic complications. Although both the estrogen and the progestin components have been involved, the underlying mechanisms responsible are unclear.Methods and Results-This study examined whether sex steroids promote hemostasis indirectly by increasing the procoagulant activity of blood vessels. Treatment of vascular smooth muscle cells with several progestins (progesterone, 3-keto-desogestel, gestodene, and medroxyprogesterone acetate) upregulated proteolytically activatable thrombin receptor (PAR-1) expression, resulting in a potentiated thrombin-induced tissue factor expression and surface procoagulant activity. In contrast, neither the progestins levonorgestrel, norethisterone, and norgestimate nor the synthetic estrogen 17 alpha -ethinylestradiol had such effects. The effect of the stimulatory progestins, which induce glucocorticoid-like effects in several cell systems, was mimicked by dexamethasone and inhibited by the progesterone and glucocorticoid receptor antagonist RU-38486. In addition, long-term administration of progesterone, 3-keto-desogestrel, or medroxyprogesterone acetate to ovariectomized rats increased PAR-1 protein level in the arterial wall, resulting in an increased responsiveness of isolated aortic rings to thrombin.Conclusions-These data demonstrate that several progestins markedly potentiate the vascular procoagulant effects of thrombin by increasing the availability of membrane thrombin receptors in the smooth muscle, an effect that is most likely due to their glucocorticoid-like activity.