Li Zhenyu, Xi Xiaodong, Gu Minyi, Feil Robert, Ye Richard D, Eigenthaler Martin, Hofmann Franz, Du Xiaoping
Department of Pharmacology, College of Medicine, University of Illinois, 835 South Wolcott Avenue, Chicago, IL 60612, USA.
Cell. 2003 Jan 10;112(1):77-86. doi: 10.1016/s0092-8674(02)01254-0.
It is currently accepted that cGMP-dependent protein kinase (PKG) inhibits platelet activation. Here, we show that PKG plays an important stimulatory role in platelet activation. Expression of recombinant PKG in a reconstituted cell model enhanced von Willebrand factor (vWF)-induced activation of the platelet integrin alpha(IIb)beta(3). PKG knockout mice showed impaired platelet responses to vWF or low doses of thrombin and prolonged bleeding time. Human platelet aggregation induced by vWF or low-dose thrombin was inhibited by PKG inhibitors but enhanced by cGMP. Furthermore, a cGMP-enhancing agent, sildenafil, promoted vWF- or thrombin-induced platelet aggregation. The cGMP-stimulated platelet responses are biphasic, consisting of an initial transient stimulatory response that promotes platelet aggregation and a subsequent inhibitory response that limits the size of thrombi.
目前普遍认为，环磷酸鸟苷（cGMP）依赖性蛋白激酶（PKG）可抑制血小板活化。在此，我们表明PKG在血小板活化中发挥重要的刺激作用。在重构细胞模型中重组PKG的表达增强了血管性血友病因子（vWF）诱导的血小板整合素α（IIb）β（3）的活化。PKG基因敲除小鼠对vWF或低剂量凝血酶的血小板反应受损，出血时间延长。vWF或低剂量凝血酶诱导的人血小板聚集受到PKG抑制剂的抑制，但cGMP可增强其聚集。此外，一种增强cGMP的药物西地那非可促进vWF或凝血酶诱导的血小板聚集。cGMP刺激的血小板反应具有双相性，包括促进血小板聚集的初始短暂刺激反应和限制血栓大小的后续抑制反应。
