Enhanced Thrombotic Responses Are Associated With Striatin Deficiency and Aldosterone.
Enhanced Thrombotic Responses Are Associated With Striatin Deficiency and Aldosterone.
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DOI：
10.1161/jaha.121.022975
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发表时间：
2021-11-16
影响因子：
5.4
通讯作者：
Romero JR
中科院分区：
文献类型：
--
作者：
Gromotowicz-Poplawska A;Flaumenhaft R;Gholami SK;Merrill-Skoloff G;Chabielska E;Williams GH;Romero JR
除了对血压的作用外，醛固酮（ALDO）还影响止血系统，导致实验性血栓形成增加。纹状体蛋白是ALDO快速非基因组作用的中间体。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有关。 将Strn+/-小鼠和野生型同窝仔维持在自由钠饮食（1.6%）上。我们使用活体显微镜测量了激光诱导的提睾肌小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或其媒介物。与对照组相比，野生型小鼠中ALDO在几分钟内可急性增加血栓形成反应（P<0.01），这通过激光损伤部位血小板聚集和纤维蛋白沉积增加来确定。然后，我们比较了在没有ALDO给药的情况下，Strn+/-和野生型小鼠中的血栓形成。Strn+/-小鼠在激光诱导的血栓形成中表现出高度显著的增加（P<0.001），如血小板聚集和纤维蛋白沉积增加所示。有趣的是，在基础上，Strn+/-小鼠中的反应远大于ALDO给药的野生型小鼠，并且ALDO给药对Strn+/-小鼠中的血栓反应没有产生额外的影响。这些结果表明，一种新的保护作用的纹状体在实验性血栓形成。这种保护作用可能在人类纹状体蛋白风险等位基因携带者中降低，因为这些个体和Strn+/-小鼠中血压的盐敏感性相似。
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. 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. 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.