Irreversible Platelet Activation Requires Protease-Activated Receptor 1-Mediated Signaling to Phosphatidylinositol Phosphates
Irreversible Platelet Activation Requires Protease-Activated Receptor 1-Mediated Signaling to Phosphatidylinositol Phosphates
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DOI：
10.1124/mol.109.056622
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发表时间：
2009-08-01
影响因子：
3.6
通讯作者：
Hamm, Heidi E.
中科院分区：
文献类型：
--
作者：
Holinstat, Michael;Preininger, Anita M.;Hamm, Heidi E.
凝血酶通过血小板聚集的早期可逆阶段诱导血小板活化，随后是血小板聚集的后期不可逆阶段。如果不进行干预，导致病理性血小板活化的事件可导致血管闭塞、急性冠状动脉综合征和中风。因此，更好地了解导致血小板介导的凝块形成的事件可能会提供新的治疗靶点。一旦激活，蛋白酶激活受体（PAR）在调节导致血小板聚集的事件中是必需的。我们已经确定了通过PAR 1的信号级联，其涉及磷脂酰肌醇（PI）激酶，磷脂酰肌醇二磷酸（PIP 2），和Rap 1激活（独立于P2 Y12）在形成稳定的血小板聚集体。通过质谱法发现，推定的磷脂酰肌醇-3激酶（PI 3 K）抑制剂LY 294002可降低基础和PAR刺激的PIP 2水平，并抑制PAR 1介导的稳定血小板聚集。Rap 1在血小板中的激活（在对应于晚期不可逆聚集期的时间点）被发现需要PI信号通路。异构体选择性抑制剂对PI 3 K信号传导的干扰通过PAR 1和PAR 4对Rap 1活化具有不同的影响。因此，有可能破坏参与稳定凝块形成的脂质信号通路而不抑制早期凝块形成，为抗血小板治疗提供了新的潜在靶点。
Thrombin induces platelet activation through an early, reversible stage of platelet aggregation, which is followed by a later, irreversible stage of platelet aggregation. Without intervention, events leading to pathological platelet activation can result in vessel occlusion, acute coronary syndrome, and stroke. Therefore, a better understanding of events leading to platelet-mediated clot formation may provide insight into new therapeutic targets. Once activated, protease activated receptors (PARs) are essential in regulating events leading to platelet aggregation. We have determined a signaling cascade through PAR1, which involves phosphatidylinositol (PI) kinases, phosphatidylinositol bisphosphate (PIP2), and Rap1 activation (independent of P2Y12) in the formation of a stable platelet aggregate. The putative phosphatidylinositol-3 kinase (PI3K) inhibitor LY294002 was found to reduce basal and PAR-stimulated PIP2 levels by mass spectrometry and to inhibit PAR1-mediated stable platelet aggregation. Rap1 activation in platelets (during time points corresponding to the late, irreversible phase of aggregation) was found to require the PI signaling pathway. Perturbation of PI3K signaling by isoform-selective inhibitors had differential effects on Rap1 activation through PAR1 and PAR4. Hence, it is possible to disrupt lipid signaling pathways involved in stable clot formation without inhibiting early clot formation, offering a new potential target for antiplatelet therapy.