Sex differences in thrombosis in mice are mediated by sex-specific growth hormone secretion patterns.
Sex differences in thrombosis in mice are mediated by sex-specific growth hormone secretion patterns.
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DOI：
10.1172/jci34957
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发表时间：
2008-08
期刊：
影响因子：
--
通讯作者：
J. H. Wong;J. Dukes;R. Levy;B. Sos;Sara Mason;Tina S. Fong;E. Weiss
中科院分区：
文献类型：
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作者：
J. H. Wong;J. Dukes;R. Levy;B. Sos;Sara Mason;Tina S. Fong;E. Weiss
血栓形成中的性别差异被很好地描述，但其潜在的机制(S)还不完全清楚。凝血蛋白是在肝脏中合成的，肝脏基因的表达具有性别特异性，并取决于生长激素(GH)分泌的性别差异--男性以脉动方式分泌GH，而女性持续分泌GH。因此，我们测试了性别特定的生长激素分泌模式导致血栓形成性别差异的假设。在凝血酶诱导的肺栓塞模型中，雄性小鼠比雌性小鼠更容易发生血栓形成，并且在体外表现出更短的凝血时间。GH缺乏的小鼠(LIT)免受血栓形成的保护，给予LIT小鼠脉冲式GH可恢复雄性凝血表型。此外，脉冲式GH给药在对照组雌性小鼠中产生雄性凝血表型，而持续GH在对照组雄性小鼠中引起雌性凝血表型。凝血抑制因子proc、Serpinc1、Serpind1和Serpina5的表达受性别特异性GH模式的强烈调控，GH调节对激活蛋白C的抵抗。这些结果揭示了一种新的机制，即性别特异性GH模式通过肝脏凝血抑制基因表达的协调变化来调节血栓形成中的性别差异。
Sex differences in thrombosis are well described, but their underlying mechanism(s) are not completely understood. Coagulation proteins are synthesized in the liver, and liver gene expression is sex specific and depends on sex differences in growth hormone (GH) secretion--males secrete GH in a pulsatile fashion, while females secrete GH continuously. Accordingly, we tested the hypothesis that sex-specific GH secretion patterns cause sex differences in thrombosis. Male mice were more susceptible to thrombosis than females in the thromboplastin-induced pulmonary embolism model and showed shorter clotting times ex vivo. GH-deficient little (lit) mice were protected from thrombosis, and pulsatile GH given to lit mice restored the male clotting phenotype. Moreover, pulsatile GH administration resulted in a male clotting phenotype in control female mice, while continuous GH caused a female clotting phenotype in control male mice. Expression of the coagulation inhibitors Proc, Serpinc1, Serpind1, and Serpina5 were strongly modulated by sex-specific GH patterns, and GH modulated resistance to activated protein C. These results reveal what we believe to be a novel mechanism whereby sex-specific GH patterns mediate sex differences in thrombosis through coordinated changes in the expression of coagulation inhibitor genes in the liver.