Platelet-derived S100 family member myeloid-related protein-14 regulates thrombosis
Yunmei Wang, … , Alvin H. Schmaier, Daniel I. Simon
Yunmei Wang, … , Alvin H. Schmaier, Daniel I. Simon
Published April 1, 2014
Citation Information: J Clin Invest. 2014;124(5):2160-2171. https://doi.org/10.1172/JCI70966.
View: Text | PDF
Research Article Hematology

Platelet-derived S100 family member myeloid-related protein-14 regulates thrombosis

Abstract

Expression of the gene encoding the S100 calcium–modulated protein family member MRP-14 (also known as S100A9) is elevated in platelets from patients presenting with acute myocardial infarction (MI) compared with those from patients with stable coronary artery disease; however, a causal role for MRP-14 in acute coronary syndromes has not been established. Here, using multiple models of vascular injury, we found that time to arterial thrombotic occlusion was markedly prolonged in Mrp14–/– mice. We observed that MRP-14 and MRP-8/MRP-14 heterodimers (S100A8/A9) are expressed in and secreted by platelets from WT mice and that thrombus formation was reduced in whole blood from Mrp14–/– mice. Infusion of WT platelets, purified MRP-14, or purified MRP-8/MRP-14 heterodimers into Mrp14–/– mice decreased the time to carotid artery occlusion after injury, indicating that platelet-derived MRP-14 directly regulates thrombosis. In contrast, infusion of purified MRP-14 into mice deficient for both MRP-14 and CD36 failed to reduce carotid occlusion times, indicating that CD36 is required for MRP-14–dependent thrombosis. Our data identify a molecular pathway of thrombosis that involves platelet MRP-14 and CD36 and suggest that targeting MRP-14 has potential for treating atherothrombotic disorders, including MI and stroke.

Authors

Yunmei Wang, Chao Fang, Huiyun Gao, Matthew L. Bilodeau, Zijie Zhang, Kevin Croce, Shijian Liu, Toshifumi Morooka, Masashi Sakuma, Kohsuke Nakajima, Shuichi Yoneda, Can Shi, David Zidar, Patrick Andre, Gillian Stephens, Roy L. Silverstein, Nancy Hogg, Alvin H. Schmaier, Daniel I. Simon

×

Figure 1

MRP-14 deficiency prolongs thrombotic occlusion time.

Options: View larger image (or click on image) Download as PowerPoint
MRP-14 deficiency prolongs thrombotic occlusion time. (A) Occlusion time...
(A) Occlusion times following photochemical injury of the carotid artery in WT and Mrp14–/– mice (mean ± SD, n = 16 per group). (B) Histologic sections of nonperfused and perfusion-fixed carotid arteries 25 minutes after injury demonstrating occlusive thrombus in WT arteries and patency in Mrp14–/–arteries. (C) Immunohistochemistry of MRP-14 and the platelet-specific marker GPIIb after carotid artery photochemical injury. (D) Thrombus formation in vivo after laser-induced injury to the arteriolar wall in the cremaster microcirculation of Mrp14–/– mice was compared with that of WT mice using intravital microscopy (see Supplemental Videos 1 and 2). Platelets were labeled in vivo using an FITC-conjugated rat anti-mouse CD41 antibody. Representative intravital images at indicated times following laser pulse. Scale bars: 50 μm (B) and 20 μm (C and D). (E) Continuous, real-time thrombosis profiles of one representative experiment (n = 10–15 arterioles per group).