Chang He Benny, Gao Xin, Nepomuceno Rachel, Hu Shaoshan, Sun Dandan
Department of Neurology, University of Pittsburgh, USA.
Department of Neurology, University of Pittsburgh, USA; Dept. of Neurological Surgery, The Second Affiliated Hospital of the Harbin Medical University, Harbin 150086, China.
Exp Neurol. 2015 Oct;272:11-6. doi: 10.1016/j.expneurol.2014.12.023. Epub 2015 Jan 13.
Platelets are anucleated cell fragments derived from mature megakaryocytes and function in hemostasis when the endothelium is injured. Hemostasis involving platelets can be divided into four phases: adhesion, activation, secretion, and aggregation. Platelet activation requires a rise in intracellular Ca(2+) concentrations and results in both a morphological change and the secretion of platelet granule contents. Na(+)/H(+) exchanger isoform 1 (NHE1) regulates the intracellular pH (pHi) and the volume of platelets. In addition, NHE1 plays a large role in platelet activation. Thrombus generation involves NHE1 activation and an increase in [Ca(2+)]i, which results from NHE1-mediated Na(+) overload and the reversal of the Na(+)/Ca(2+) exchanger. Cariporide (HOE-642), a potent NHE1 inhibitor, has inhibitory effects on the degranulation of human platelets, the formation of platelet-leukocyte-aggregates, and the activation of the GPIIb/IIIa receptor (PAC-1). However, despite the demonstrated protection against myocardial infarction as mediated by cariporide in patients undergoing coronary artery bypass graft surgery, the EXPEDITION clinical trial revealed that cariporide treatment increased mortality due to thromboembolic stroke. These findings suggest that a better understanding of NHE1 and its effect on platelet function and procoagulant factor regulation is warranted in order to develop therapies using NHE inhibitors.
血小板是源自成熟巨核细胞的无核细胞碎片，在内皮损伤时发挥止血作用。涉及血小板的止血过程可分为四个阶段：黏附、激活、分泌和聚集。血小板激活需要细胞内Ca(2+)浓度升高，并导致形态变化和血小板颗粒内容物的分泌。钠/氢交换体同工型1（NHE1）调节血小板的细胞内pH（pHi）和体积。此外，NHE1在血小板激活中起重要作用。血栓形成涉及NHE1激活和[Ca(2+)]i增加，这是由NHE1介导的Na(+)过载和钠/钙交换体的逆转引起的。卡立泊来德（HOE-642）是一种有效的NHE1抑制剂，对人血小板脱颗粒、血小板-白细胞聚集体形成以及糖蛋白IIb/IIIa受体（PAC-1）激活具有抑制作用。然而，尽管卡立泊来德在冠状动脉搭桥手术患者中显示出对心肌梗死的保护作用，但EXPEDITION临床试验表明，卡立泊来德治疗会增加血栓栓塞性中风导致的死亡率。这些发现表明，为了开发使用NHE抑制剂的疗法，有必要更好地了解NHE1及其对血小板功能和促凝血因子调节的影响。
