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Myeloid-related protein-14 regulates deep vein thrombosis
Yunmei Wang, … , Farouc A. Jaffer, Daniel I. Simon
Yunmei Wang, … , Farouc A. Jaffer, Daniel I. Simon
Published June 2, 2017
Citation Information: JCI Insight. 2017;2(11):e91356. https://doi.org/10.1172/jci.insight.91356.
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Research Article Cardiology Vascular biology

Myeloid-related protein-14 regulates deep vein thrombosis

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Abstract

Using transcriptional profiling of platelets from patients presenting with acute myocardial infarction, we identified myeloid-related protein-14 (MRP-14, also known as S100A9) as an acute myocardial infarction gene and reported that platelet MRP-14 binding to platelet CD36 regulates arterial thrombosis. However, whether MRP-14 plays a role in venous thrombosis is unknown. We subjected WT and Mrp-14–deficient (Mrp-14-/-) mice to experimental models of deep vein thrombosis (DVT) by stasis ligation or partial flow restriction (stenosis) of the inferior vena cava. Thrombus weight in response to stasis ligation or stenosis was reduced significantly in Mrp-14-/- mice compared with WT mice. The adoptive transfer of WT neutrophils or platelets, or the infusion of recombinant MRP-8/14, into Mrp-14-/- mice rescued the venous thrombosis defect in Mrp-14-/- mice, indicating that neutrophil- and platelet-derived MRP-14 directly regulate venous thrombogenesis. Stimulation of neutrophils with MRP-14 induced neutrophil extracellular trap (NET) formation, and NETs were reduced in venous thrombi harvested from Mrp-14-/- mice and in Mrp-14-/- neutrophils stimulated with ionomycin. Given prior evidence that MRP-14 also regulates arterial thrombosis, but not hemostasis (i.e., reduced bleeding risk), MRP-14 appears to be a particularly attractive molecular target for treating thrombotic cardiovascular diseases, including myocardial infarction, stroke, and venous thromboembolism.

Authors

Yunmei Wang, Huiyun Gao, Chase W. Kessinger, Alvin Schmaier, Farouc A. Jaffer, Daniel I. Simon

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Figure 1

Deep vein thrombus formation is attenuated in Mrp-14-/- mice.

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Deep vein thrombus formation is attenuated in Mrp-14-/- mice.
Inferior v...
Inferior vena cava (IVC) thrombus weight (mg) of individual mice after deep vein thrombosis (DVT) induction. (A) Two days after IVC ligation (stasis) in WT (n = 10) and Mrp-14-/- (n = 11) mice. Representative images of WT and Mrp-14-/- thrombi (n = 10–11). (B) Two days after IVC partial flow restriction (stenosis) in WT (n = 8) and Mrp-14-/- (n = 8) mice. (C) Four days after IVC ligation (stasis) in WT (n = 8) and Mrp-14-/- (n = 6) mice. (D) Twelve days after IVC ligation (stasis) in WT (n = 6) and Mrp-14-/- (n = 7) mice. (E) Representative image of hind limbs of WT (left) and Mrp-14-/- (right) mice 12 days after IVC ligation (stasis). Each dot represents 1 mouse. Data represent mean ± SD. P values were obtained by conducting unpaired, 2-tailed t test using Excel.

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