Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Thromb Haemost. 2020 Oct;120(10):1417-1431. doi: 10.1055/s-0040-1714278. Epub 2020 Sep 2.
Arterial thrombosis is initiated by atherosclerotic plaque damage, prothrombotic material release and platelet aggregation. Platelets are primary mediators involved in thrombosis and cooperate with vascular and immune cells.
Herein, we investigated how activated platelets interacted with monocytes in atherothrombosis.
We collected patients' blood from coronary arteries during percutaneous coronary intervention and measured platelet activity. Platelets from coronary arteries had higher pseudopodium expression and activity in patients with acute coronary syndrome (ACS). Ribosome profiling of platelets from coronary blood mapped a vigorous upregulation of Rho GTPases and their downstream effectors. RhoA activated downstream Rho-associated coiled-coil containing protein kinase (ROCK), and ROCK increased surface P-selectin in coronary blood platelets. The interaction between platelets and monocytes was observed in vitro, and was found in ruptured coronary plaques of ACS. Further we found that activated platelets promoted monocytes transmigration, which could be suppressed in the presence of ROCK inhibitors. The increased surface P-selectin on thrombin-induced platelets interacted with monocytes to upregulate monocyte chemokine receptor 2 (CCR2) expression via the ROCK pathway. The expression of CCR2 was higher in monocyte-platelet aggregates than in monocytes without platelets. Finally, using the Asian Screening Array BeadChip, we identified single-nucleotide polymorphism (SNP) associated with cardiovascular events. Notably, patients having homozygous major alleles of the SNP rs11706370 presented with higher risks of cardiovascular events.
Through ROCK-activated cytoskeleton remodeling and P-selectin expression, platelets were recruited and interacted synergistically with high CCR2-expressing monocytes to induce thromboinflammation in atherothrombosis.
动脉血栓形成是由动脉粥样硬化斑块损伤、促血栓形成物质释放和血小板聚集引发的。血小板是参与血栓形成的主要介质，与血管和免疫细胞合作。
本文旨在研究活化血小板在动脉血栓形成中与单核细胞的相互作用。
我们从经皮冠状动脉介入治疗患者的冠状动脉中采集血液，测量血小板活性。急性冠状动脉综合征（ACS）患者冠状动脉中的血小板具有更高的伪足表达和活性。冠状动脉血小板的核糖体图谱显示 Rho GTPases 及其下游效应物的强烈上调。RhoA 激活下游的 Rho 相关卷曲螺旋蛋白激酶（ROCK），ROCK 增加冠状动脉血小板表面的 P-选择素。在体外观察到血小板与单核细胞的相互作用，并在 ACS 破裂的冠状动脉斑块中发现。此外，我们发现活化的血小板促进单核细胞迁移，而 ROCK 抑制剂可抑制这种迁移。凝血酶诱导的血小板表面 P-选择素增加，与单核细胞相互作用，通过 ROCK 通路上调单核细胞趋化因子受体 2（CCR2）表达。血小板-单核细胞聚集体中的 CCR2 表达高于无血小板的单核细胞。最后，使用亚洲筛选阵列珠芯片，我们鉴定出与心血管事件相关的单核苷酸多态性（SNP）。值得注意的是，SNP rs11706370 的纯合主要等位基因患者发生心血管事件的风险更高。
通过 ROCK 激活的细胞骨架重塑和 P-选择素表达，血小板被募集并与高表达 CCR2 的单核细胞协同作用，在动脉血栓形成中诱导血栓炎症。
