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.
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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

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Figure 7

CD36 is required for MRP-14 action.

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CD36 is required for MRP-14 action. (A) Binding of purified MRP-14 (0–2....
(A) Binding of purified MRP-14 (0–2.5 μg/ml) to purified soluble CD36-coated or BSA-coated wells. (B) Thrombotic occlusion time after carotid artery photochemical injury in indicated mouse strains and occlusion time with intravenous infusion of saline or purified human MRP-14 (0.08 μg/g mouse) into Mrp14–/– or Mrp14–/– Cd36–/– recipient mice prior to photochemical injury. (C) Purified MRP-14 restores platelet thrombus formation under flow in Mrp14–/–, but not Mrp14–/–Cd36–/–, murine whole blood. Platelet thrombi on collagen-coated capillaries following perfusion (shear rate of 625 s–1) of rhodamine 6G–labeled Mrp14–/– blood from WT, Mrp14–/–, or Mrp14–/–Cd36–/– mice that was treated with purified human MRP-14 (5 μg/ml) or control buffer. Original magnification, ×40; observation area, 360 × 270 mm. (D) Continuous, real-time thrombosis profiles of the average fluorescence of three independent experiments. MRP-14 induced phosphorylation of VAV (E) and JNK (F) in platelets. Gel-filtered human platelets (2 × 108/ml) containing 2 mM CaCl2 and 1 mM MgCl2 were incubated with 50 μg/ml oxLDL, 1 μg/ml MRP-14, or a combination of these for 10 minutes, and platelet lysates were analyzed by immunoblotting with anti-phosphoprotein antibodies. The membranes were then stripped and reprobed with antibodies against the total relevant protein and actin. Results are representative of three independent experiments from different donors.