Leger Andrew J, Covic Lidija, Kuliopulos Athan
Hemostasis and Thrombosis Laboratory, Division of Hematology/Oncology, Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, MA 02111, USA.
Circulation. 2006 Sep 5;114(10):1070-7. doi: 10.1161/CIRCULATIONAHA.105.574830.
Thrombosis associated with the pathophysiological activation of platelets and vascular cells has brought thrombin and its receptors to the forefront of cardiovascular medicine. Thrombin signaling through the protease-activated receptors (PARs) has been shown to influence a wide range of physiological responses including platelet activation, intimal hyperplasia, inflammation, and maintenance of vascular tone and barrier function. The thrombin receptors PAR1 and PAR4 can be effectively targeted in animals in which acute or prolonged exposure to thrombin leads to thrombosis and/or restenosis. In the present study, we describe the molecular and pharmacological basis of small-molecule inhibitors that target PAR1. In addition, we discuss a new class of cell-penetrating inhibitors, termed pepducins, that provide insight into previously unidentified roles of PAR1 and PAR4 in protease signaling.
与血小板和血管细胞的病理生理激活相关的血栓形成，已使凝血酶及其受体成为心血管医学的前沿研究对象。通过蛋白酶激活受体（PARs）进行的凝血酶信号传导，已被证明可影响多种生理反应，包括血小板激活、内膜增生、炎症以及血管张力和屏障功能的维持。在动物模型中，急性或长期暴露于凝血酶会导致血栓形成和/或再狭窄，而凝血酶受体PAR1和PAR4可成为有效靶点。在本研究中，我们描述了靶向PAR1的小分子抑制剂的分子和药理学基础。此外，我们还讨论了一类新型的细胞穿透抑制剂，即肽模拟物，它们为PAR1和PAR4在蛋白酶信号传导中以前未被识别的作用提供了新的见解。
