Peroxiredoxin II is an antioxidant enzyme that negatively regulates collagen-stimulated platelet function [Cell Biology]

March 23rd, 2015 by Jang, J. Y., Wang, S. B., Min, J. H., Chae, Y. H., Baek, J. Y., Yu, D.-Y., Chang, T.-S.

Collagen-induced platelet signaling is mediated by binding to the primary receptor glycoprotein VI (GPVI). Reactive oxygen species (ROS) produced in response to collagen has been found to be responsible for the propagation of GPVI signaling pathways in platelets. Thus, it has been suggested that antioxidant enzymes could downregulate GPVI-stimulated platelet activation. Although the antioxidant enzyme peroxiredoxin II (PrxII) has emerged as having a role in negatively regulating the signaling through various receptors by eliminating H2O2 generated upon receptor stimulation, the function of PrxII in collagen-stimulated platelets is not known. We tested the hypothesis that PrxII negatively regulates collagen-stimulated platelet activation. We analyzed PrxII-deficient murine platelets. PrxII-deficiency enhanced GPVI-mediated platelet activation through the defective elimination of H2O2 and the impaired protection of SH2 domain-containing tyrosine phosphatase-2 (SHP-2) against oxidative inactivation, which resulted in increased tyrosine phosphorylation of key components for GPVI signaling cascade, including Syk, Btk and phospholipase Cγ2. Interestingly, PrxII-mediated antioxidative protection of SHP-2 appeared to occur in the lipid rafts. PrxII-deficient platelets exhibited increased adhesion and aggregation upon collagen. Furthermore, in vivo experiments demonstrated that PrxII-deficiency facilitated platelet-dependent thrombus formation in injured carotid arteries. This study reveals that PrxII functions as a protective antioxidant enzyme against collagen-stimulated platelet activation and platelet-dependent thrombosis.