Abstract
Collagen-induced platelet signaling is mediated by binding to the primary receptor glycoprotein VI (GPVI). Reactive oxygen species produced in response to collagen have been found to be responsible for the propagation of GPVI signaling pathways in platelets. Therefore, it has been suggested that antioxidant enzymes could down-regulate GPVI-stimulated platelet activation. Although the antioxidant enzyme peroxiredoxin II (PrxII) has emerged as having a role in negatively regulating 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 the 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 stimulation. 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.
Highlights
Peroxiredoxin II (PrxII) functions as a negative regulator of cellular receptor signaling by efficiently eliminating H2O2 produced upon stimulation of receptors
We found that PrxII deficiency significantly enhanced glycoprotein VI (GPVI)-stimulated platelet activation through the defective elimination of H2O2 and the impaired protection of SH2 domain-containing tyrosine phosphatase 2 (SHP-2) from oxidative inactivation, which led to increased tyrosine phosphorylation of key components of the GPVI signaling cascade
Hyperactive platelets underlie the pathophysiology of vascular diseases such as thrombosis and atherosclerosis because endothelial injury leads to the adhesion of platelets to the subendothelial collagen via GPVI, the primary collagen receptor on platelets [4]
Summary
Peroxiredoxin II (PrxII) functions as a negative regulator of cellular receptor signaling by efficiently eliminating H2O2 produced upon stimulation of receptors. 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 the GPVI signaling cascade, including Syk, Btk, and phospholipase C␥2. When stimulated with platelet-derived growth factor, cells derived from PrxII-deficient mice have been found to exhibit enhanced tyrosine phosphorylation of platelet-derived growth factor receptor, demonstrating that one function of PrxII is to protect the lipid raft-associated PTPs from oxidative inactivation by removing H2O2 [18]. We found that PrxII deficiency significantly enhanced GPVI-stimulated platelet activation through the defective elimination of H2O2 and the impaired protection of SHP-2 from oxidative inactivation, which led to increased tyrosine phosphorylation of key components of the GPVI signaling cascade. We validated the antithrombotic activity of PrxII in vivo using an arterial injury model
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