Cardeza Foundation for Hematological Research, Thomas Jefferson University, Jefferson Alumni Hall, 1020 Locust Street, Philadelphia, PA 19107, USA.
Cardeza Foundation for Hematological Research, Thomas Jefferson University, Jefferson Alumni Hall, 1020 Locust Street, Philadelphia, PA 19107, USA.
Thromb Res. 2021 Jun;202:67-73. doi: 10.1016/j.thromres.2021.03.003. Epub 2021 Mar 8.
PCTP (phosphatidylcholine transfer protein) was discovered recently to regulate aggregation of human platelets stimulated with PAR4 activating peptide (PAR4AP). However, the role of PCTP following thrombin stimulation, the mechanisms by which PCTP contributes to platelet activation, and the role of PCTP with other receptors remained unknown. As mouse platelets do not express PCTP, we treated human platelets with various agonists in the presence of the specific PCTP inhibitor A1. We observed that PCTP inhibition significantly reduced dense granule secretion in response to thrombin, PAR1AP, PAR4AP, convulxin (GPVI agonist) and FcγRIIA crosslinking. In contrast, among these agonists, PCTP inhibition reduced aggregation only to low dose thrombin and PAR4AP. Unlike its effects on dense granule secretion, PCTP inhibition did not reduce alpha granule secretion in response to thrombin or PAR4AP. PCTP inhibition reduced both the increase in cytoplasmic Ca as well as PKC activity downstream of thrombin. These data are consistent with PCTP contributing to secretion of dense granules, and to being particularly important to human PAR4 early signaling events. Future studies will address further these molecular mechanisms and consequences for hemostasis and thrombosis.
PCTP（磷酸甘油酯转移蛋白）最近被发现可调节人血小板在 PAR4 激活肽（PAR4AP）刺激下的聚集。然而，在凝血酶刺激后 PCTP 的作用、PCTP 促进血小板激活的机制以及 PCTP 与其他受体的作用仍不清楚。由于小鼠血小板不表达 PCTP，我们在特定的 PCTP 抑制剂 A1 存在的情况下用各种激动剂处理人血小板。我们观察到，PCTP 抑制显著减少了对凝血酶、PAR1AP、PAR4AP、凝聚素（GPVI 激动剂）和 FcγRIIA 交联的致密颗粒分泌。相比之下，在这些激动剂中，PCTP 抑制仅减少了低剂量凝血酶和 PAR4AP 的聚集。与对致密颗粒分泌的影响不同，PCTP 抑制并没有减少对凝血酶或 PAR4AP 的α颗粒分泌。PCTP 抑制减少了凝血酶下游细胞质 Ca 的增加和 PKC 活性。这些数据表明 PCTP 有助于致密颗粒的分泌，并且对人 PAR4 的早期信号事件尤为重要。未来的研究将进一步探讨这些分子机制及其对止血和血栓形成的影响。
