Platelet heterogeneity in activation-induced glycoprotein shedding: functional effects
Platelet heterogeneity in activation-induced glycoprotein shedding: functional effects
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DOI：
10.1182/bloodadvances.2017011544
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发表时间：
2018-09-25
期刊：
影响因子：
7.5
通讯作者：
Heemskerk, Johan W. M.
中科院分区：
文献类型：
--
作者：
Baaten, Constance C. F. M. J.;Swieringa, Frauke;Heemskerk, Johan W. M.
已知血小板受体糖蛋白 Ib α (GPIb α) 和 GPVI 会被解整合素和金属蛋白酶 (ADAM) 家族的成员（ADAM10 和 ADAM17）裂解，但这种脱落的机制和后果尚不清楚。我们的结果表明，(1) 糖蛋白脱落仅限于表现出接近完全脱落的不同血小板群体，(2) （非）脱落血小板之间的异质性与激动剂类型无关，但与磷脂酰丝氨酸 (PS) 的暴露一致，(3) 不同的脱落途径是由 Ca2+ 升高、Ca2+ 蛋白激酶 C (PKC) 降低或细胞凋亡激活诱导的。此外，我们发现受体脱落减少了血管性血友病因子的结合，增强了凝血因子的结合，并增加了纤维蛋白的形成。作为对 Ca2+ 增加剂的反应，GPIba 的脱落被 ADAM10/17 抑制所消除，但不能被钙蛋白酶阻断所消除。刺激 PKC 仅诱导 GPIba 脱落，但通过激酶抑制可消除这种脱落。促凋亡剂 ABT-737 诱导脱落，这是半胱天冬酶依赖性的。在缺乏 Ca2+ 依赖性 PS 暴露的 Scott 综合征血小板中，脱落正常发生，表明 PS 暴露不是 ADAM 活性的先决条件。在全血血栓形成中，ADAM 依赖性糖蛋白脱落增强了凝血酶的生成和纤维蛋白的形成。总之，这些发现表明，两种主要的激活途径可以在不同的血小板群体中引起 ADAM 介导的糖蛋白脱落，并且脱落调节血小板功能，从粘附性较低到促凝血性较高。
The platelet receptors glycoprotein Ib alpha (GPIb alpha) and GPVI are known to be cleaved by members of a disintegrin and metalloprotease (ADAM) family (ADAM10 and ADAM17), but the mechanisms and consequences of this shedding are not well understood. Our results revealed that (1) glycoprotein shedding is confined to distinct platelet populations showing near-complete shedding, (2) the heterogeneity between (non) shed platelets is independent of agonist type but coincides with exposure of phosphatidylserine (PS), and (3) distinct pathways of shedding are induced by elevated Ca2+, low Ca2+ protein kinase C (PKC), or apoptotic activation. Furthermore, we found that receptor shedding reduces binding of von Willebrand factor, enhances binding of coagulation factors, and augments fibrin formation. In response to Ca2+-increasing agents, shedding of GPIba was abolished by ADAM10/17 inhibition but not by blockage of calpain. Stimulation of PKC induced shedding of only GPIba, which was annulled by kinase inhibition. The proapoptotic agent ABT-737 induced shedding, which was caspase dependent. In Scott syndrome platelets that are deficient in Ca2+-dependent PS exposure, shedding occurred normally, indicating that PS exposure is not a prerequisite for ADAM activity. In whole-blood thrombus formation, ADAM-dependent glycoprotein shedding enhanced thrombin generation and fibrin formation. Together, these findings indicate that 2 major activation pathways can evoke ADAM-mediated glycoprotein shedding in distinct platelet populations and that shedding modulates platelet function from less adhesive to more procoagulant.