Abstract:
Background In addition to its role on blood pressure, aldosterone (ALDO) also affects the hemostatic system leading to increased experimental thrombosis. Striatin is an intermediate in the rapid, nongenomic actions of ALDO. Striatin heterozygote knockout (Strn+/-) mice have salt sensitivity of blood pressure and mildly chronically increased ALDO levels. In addition, in humans, striatin polymorphic gene variants are associated with increased salt sensitivity of blood pressure. Thus, we hypothesized that striatin deficiency would be associated with an increased prothrombotic response. Methods and Results Strn+/ - mice and wild-type littermates were maintained on a liberal sodium diet (1.6%). We measured in vivo thrombus formation following laser-induced injury in cremaster arterioles using intravital microscopy. Mice were randomized to intravenous administration of ALDO or its vehicle. Acutely, ALDO increased thrombotic responses in wild-type mice (P<0.01) versus controls within minutes as determined by increased platelet accumulation and fibrin deposition at the site of laser injury. We then compared thrombus formation without ALDO administration in Strn+/- and wild-type mice. Strn+/- mice showed highly significant increases in laser-induced thrombosis (P<0.001), as shown by increased platelet accumulation and fibrin deposition. Interestingly, the response in the Strn+/- mice basally was far greater than the wild-type mice with ALDO administration, and ALDO administration produced no additional effect on thrombus responses in Strn+/- mice. Conclusions These results demonstrate a novel protective role of striatin in experimental thrombosis. Such a protective effect may be reduced in human striatin risk allele carriers, given the similar salt sensitivity of blood pressure in these individuals and Strn+/- mice.
摘要:
背景除了它对血压的作用外,醛固酮(ALDO)也会影响止血系统,导致实验性血栓形成增加。纹状体是快速的中间体,ALDO的非基因组作用。纹状体蛋白杂合子敲除(Strn+/-)小鼠具有血压的盐敏感性和轻度慢性增加的ALDO水平。此外,在人类中,纹状体蛋白多态性基因变异与血压的盐敏感性增加有关。因此,我们假设纹状体蛋白缺乏与血栓前反应增加相关.方法和结果Strn+/-小鼠和野生型同窝动物维持自由钠饮食(1.6%)。我们使用活体显微镜测量了激光诱导的微动脉损伤后的体内血栓形成。将小鼠随机化以静脉内施用ALDO或其载体。绝对,如通过在激光损伤部位处增加的血小板积聚和纤维蛋白沉积所确定的,ALDO在数分钟内相对于对照在野生型小鼠中增加的血栓形成反应(P<0.01)。然后我们比较了Strn+/-和野生型小鼠中没有ALDO给药的血栓形成。Strn+/-小鼠激光诱导的血栓形成显著增加(P<0.001),如血小板积累和纤维蛋白沉积增加所示。有趣的是,在Strn+/-小鼠基础上的反应远远大于使用ALDO的野生型小鼠,和ALDO给药对Strn+/-小鼠的血栓反应没有产生额外的影响。结论这些结果证明了纹状体蛋白在实验性血栓形成中的新的保护作用。在人类纹状体蛋白风险等位基因携带者中,这种保护作用可能会降低,考虑到这些个体和Strn+/-小鼠的血压盐敏感性相似。