Divisions of Cardiology and Hematology, Department Medicine, New York University School of Medicine, New York, New York.
Division of Vascular Surgery, Department of Surgery, New York University School of Medicine, New York, New York.
J Am Coll Cardiol. 2018 Jan 2;71(1):53-65. doi: 10.1016/j.jacc.2017.10.072.
Peripheral artery disease (PAD), a diffuse manifestation of atherothrombosis, is a major cardiovascular threat. Although platelets are primary mediators of atherothrombosis, their role in the pathogenesis of PAD remains unclear.
The authors sought to investigate the role of platelets in a cohort of symptomatic PAD.
The authors profiled platelet activity, mRNA, and effector roles in patients with symptomatic PAD and in healthy controls. Patients with PAD and carotid artery stenosis were recruited into ongoing studies (NCT02106429 and NCT01897103) investigating platelet activity, platelet RNA, and cardiovascular disease.
Platelet RNA sequence profiling mapped a robust up-regulation of myeloid-related protein (MRP)-14 mRNA, a potent calcium binding protein heterodimer, in PAD. Circulating activated platelets were enriched with MRP-14 protein, which augmented the expression of the adhesion mediator, P-selectin, thereby promoting monocyte-platelet aggregates. Electron microscopy confirmed the firm interaction of platelets with monocytes in vitro and colocalization of macrophages with MRP-14 confirmed their cross talk in atherosclerotic manifestations of PAD in vivo. Platelet-derived MRP-14 was channeled to monocytes, thereby fueling their expression of key PAD lesional hallmarks and increasing their directed locomotion, which were both suppressed in the presence of antibody-mediated blockade. Circulating MRP-14 was heightened in the setting of PAD, significantly correlated with PAD severity, and was associated with incident limb events.
The authors identified a heightened platelet activity profile and unraveled a novel immunomodulatory effector role of platelet-derived MRP-14 in reprograming monocyte activation in symptomatic PAD. (Platelet Activity in Vascular Surgery and Cardiovascular Events [PACE]; NCT02106429; and Platelet Activity in Vascular Surgery for Thrombosis and Bleeding [PIVOTAL]; NCT01897103).
外周动脉疾病（PAD）是动脉粥样血栓形成的弥漫表现，是主要的心血管威胁。尽管血小板是动脉粥样血栓形成的主要介质，但它们在 PAD 发病机制中的作用仍不清楚。
作者试图研究血小板在外周动脉疾病患者中的作用。
作者对有症状的 PAD 患者和健康对照者的血小板活性、mRNA 和效应功能进行了分析。PAD 合并颈动脉狭窄的患者被招募到正在进行的研究中（NCT02106429 和 NCT01897103），这些研究旨在研究血小板活性、血小板 RNA 和心血管疾病。
血小板 RNA 序列分析显示，在 PAD 中，髓样相关蛋白（MRP）-14mRNA 显著上调，MRP-14 是一种强有力的钙结合蛋白异二聚体。循环激活的血小板富含 MRP-14 蛋白，可增强黏附分子 P-选择素的表达，从而促进单核细胞-血小板聚集物的形成。电镜证实了血小板与单核细胞在体外的牢固相互作用，并证实了巨噬细胞与 MRP-14 的共定位，这表明它们在 PAD 的动脉粥样硬化表现中存在细胞间的信号转导。血小板衍生的 MRP-14 被输送到单核细胞，从而促进其表达关键的 PAD 病变特征，并增加其定向迁移，而这两种作用在抗体介导的阻断存在时均受到抑制。在 PAD 中，MRP-14 循环水平升高，与 PAD 严重程度显著相关，并与肢体事件的发生相关。
作者确定了一种增强的血小板活性谱，并揭示了血小板源性 MRP-14 在有症状的 PAD 中重新编程单核细胞激活的新型免疫调节效应功能。（血管外科学中的血小板活性和心血管事件[PACE]；NCT02106429；血管外科学中的血小板活性用于血栓形成和出血[PIVOTAL]；NCT01897103）。
