Computational Biology Unit, Department of Informatics, University of Bergen, Thormøhlensgate 55, 5008 Bergen, Norway.
Department of Biomedicine, Proteomics Unit at University of Bergen (PROBE), University of Bergen, Jonas Lies vei 91, 5020 Bergen, Norway.
Int J Mol Sci. 2018 Feb 19;19(2):612. doi: 10.3390/ijms19020612.
Platelet activation contributes to normal haemostasis but also to pathologic conditions like stroke and cardiac infarction. Signalling by cGMP and cAMP inhibit platelet activation and are therefore attractive targets for thrombosis prevention. However, extensive cross-talk between the cGMP and cAMP signalling pathways in multiple tissues complicates the selective targeting of their activities. We have used mathematical modelling based on experimental data from the literature to quantify the steady state behaviour of nitric oxide (NO)/cGMP/cAMP signalling in platelets. The analysis provides an assessment of NO-induced cGMP synthesis and PKG activation as well as cGMP-mediated cAMP and PKA activation though modulation of phosphodiesterase (PDE2 and 3) activities. Both one- and two-compartment models of platelet cyclic nucleotide signalling are presented. The models provide new insight for understanding how NO signalling to cGMP and indirectly cAMP, can inhibit platelet shape-change, the initial step of platelet activation. Only the two-compartment models could account for the experimental observation that NO-mediated PKA activation can occur when the bulk platelet cAMP level is unchanged. The models revealed also a potential for hierarchical interplay between the different platelet phosphodiesterases. Specifically, the models predict, unexpectedly, a strong effect of pharmacological inhibitors of cGMP-specific PDE5 on the cGMP/cAMP cross-talk. This may explain the successful use of weak PDE5-inhibitors, such as dipyridamole, in anti-platelet therapy. In conclusion, increased NO signalling or PDE5 inhibition are attractive ways of increasing cGMP-cAMP cross-talk selectively in platelets.
血小板激活有助于正常止血，但也会导致病理状态，如中风和心肌梗死。cGMP 和 cAMP 的信号转导抑制血小板激活，因此是预防血栓形成的有吸引力的靶点。然而，cGMP 和 cAMP 信号通路在多种组织中的广泛串扰使它们的活性的选择性靶向复杂化。我们使用基于文献中实验数据的数学建模来量化血小板中一氧化氮（NO）/cGMP/cAMP 信号的稳态行为。该分析提供了对 NO 诱导的 cGMP 合成和 PKG 激活以及 cGMP 介导的 cAMP 和 PKA 激活的评估，通过调节磷酸二酯酶（PDE2 和 3）活性。呈现了血小板环核苷酸信号的单室和双室模型。这些模型为理解 NO 信号转导至 cGMP 并间接转导至 cAMP 如何抑制血小板形态变化（血小板激活的初始步骤）提供了新的见解。只有双室模型才能解释实验观察结果，即当血小板 cAMP 水平不变时，NO 介导的 PKA 激活可以发生。这些模型还揭示了不同血小板磷酸二酯酶之间潜在的分层相互作用。具体而言，模型预测，出乎意料的是，cGMP 特异性 PDE5 的药理学抑制剂对 cGMP/cAMP 串扰具有强烈影响。这可以解释弱 PDE5 抑制剂（如双嘧达莫）在抗血小板治疗中的成功应用。总之，增加 NO 信号或抑制 PDE5 是在血小板中选择性增加 cGMP-cAMP 串扰的有吸引力的方法。
