Abstract
NADPH oxidase (NOX) enzymes are involved in a various physiological and pathological processes such as platelet activation and inflammation. Interestingly, we found that the pan-NOX inhibitors VAS compounds (VAS2870 and its analog VAS3947) exerted a highly potent antiplatelet effect. Unlike VAS compounds, concurrent inhibition of NOX1, 2, and 4 by treatment with ML171, GSK2795039, and GKT136901/GKT137831 did not affect thrombin and U46619-induced platelet aggregation. These findings suggest that VAS compounds may inhibit platelet aggregation via a NOX-independent manner. Thus, we aimed to investigate the detailed antiplatelet mechanisms of VAS compounds. The data revealed that VAS compounds blocked various agonist-induced platelet aggregation, possibly via blocking PKC downstream signaling, including IKKβ and p38 MAPK, eventually reducing platelet granule release, calcium mobilization, and GPIIbIIIa activation. In addition, VAS compounds inhibited mouse platelet aggregation-induced by collagen and thrombin. The in vivo study also showed that VAS compounds delayed thrombus formation without affecting normal hemostasis. This study is the first to demonstrate that, in addition to inhibiting NOX activity, VAS compounds reduced platelet activation and thrombus formation through a NOX-independent pathway downstream of PKC. These findings also indicate that VAS compounds may be safe and potentially therapeutic agents for treating patients with cardiovascular diseases.
Highlights
NADPH oxidase (NOX) enzymes are involved in a various physiological and pathological processes such as platelet activation and inflammation
These results suggest that VAS compounds can inhibit G protein-coupled receptor (GPCR)- and GPVImediated platelet activation
ML171, even at high concentrations of 10 and 100 μM, did not exert an inhibitory effect on platelet aggregation induced by convulxin, thrombin, or U46619 (Figs. 2F–H; S1B–E), indicating that ML171 is sensitive to the inhibition of collagen-mediated platelet activation
Summary
NADPH oxidase (NOX) enzymes are involved in a various physiological and pathological processes such as platelet activation and inflammation. This study is the first to demonstrate that, in addition to inhibiting NOX activity, VAS compounds reduced platelet activation and thrombus formation through a NOX-independent pathway downstream of PKC. These findings indicate that VAS compounds may be safe and potentially therapeutic agents for treating patients with cardiovascular diseases. Unlike VAS compounds, concurrent inhibition of NOX1, 2, and 4 by treatment with ML171, GSK2795039, and GKT136901/GKT137831 did not affect thrombin and U46619-induced platelet aggregation These findings suggest that, in addition to serving as NOX inhibitors, VAS compounds may inhibit platelet aggregation via a NOX-independent manner. We further determined the detailed mechanisms underlying the antiplatelet effect of VAS2870 and VAS3947
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