Author + information
- Received July 27, 2017
- Revision received September 28, 2017
- Accepted October 23, 2017
- Published online January 1, 2018.
- Rebecca Dann, BSca,
- Tarik Hadi, PhDb,
- Emilie Montenont, PhDa,
- Ludovic Boytard, PhDb,
- Dornaszadat Alebrahim, MDb,
- Jordyn Feinstein, MAb,
- Nicole Allen, BSca,
- Russell Simon, MDb,
- Krista Barone, BScb,
- Kunihiro Uryu, PhDc,
- Yu Guo, MAa,
- Caron Rockman, MDb,
- Bhama Ramkhelawon, PhDb,d,∗ ( and )
- Jeffrey S. Berger, MD, MSa,b,∗∗ ()
- aDivisions of Cardiology and Hematology, Department Medicine, New York University School of Medicine, New York, New York
- bDivision of Vascular Surgery, Department of Surgery, New York University School of Medicine, New York, New York
- cElectron Microscopy Resource Center, The Rockefeller University, New York, New York
- dDepartment of Cell Biology, New York University School of Medicine, New York, New York
- ↵∗Address for correspondence:
Dr. Bhama Ramkhelawon, Division of Vascular Surgery, Department of Surgery, New York University School of Medicine, 530 First Avenue, New York, New York 10016.
- ↵∗∗Dr. Jeffrey S. Berger, Divisions of Cardiology and Hematology, Department of Medicine, New York University School of Medicine, 530 First Avenue, New York, New York 10016.
Background 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.
Objectives The authors sought to investigate the role of platelets in a cohort of symptomatic PAD.
Methods 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.
Results 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.
Conclusions 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)
This work was supported in part by the National Heart, Lung, and Blood Institute of the National Institute of Health (R00 HL125667 to Dr. Ramkhelawon) and (R01HL114978 to Dr. Berger) and the American Heart Association Clinical Research Program (13CRP14410042 to Dr. Berger). The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Ramkhelawon and Berger contributed equally to this work and are joint senior authors.
- Received July 27, 2017.
- Revision received September 28, 2017.
- Accepted October 23, 2017.
- 2018 American College of Cardiology Foundation
This article requires a subscription or purchase to view the full text. If you are a subscriber or member, click Login or the Subscribe link (top menu above) to access this article.