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Using 3KO (triple NOX [NADPH oxidase] knockout) mice (ie, NOX1^−/−/NOX2^−/−/NOX4^−/−), we aimed to clarify the role of this family of enzymes in the regulation of platelets in vitro and hemostasis in vivo.

3KO mice displayed significantly reduced platelet superoxide radical generation, which was associated with impaired platelet aggregation, adhesion, and thrombus formation in response to the key agonists collagen and thrombin. A comparison with single-gene knockouts suggested that the phenotype of 3KO platelets is the combination of the effects of the genetic deletion of NOX1 and NOX2, while NOX4 does not show any significant function in platelet regulation. 3KO platelets displayed significantly higher levels of cGMP—a negative platelet regulator that activates PKG (protein kinase G). The inhibition of PKG substantially but only partially rescued the defective phenotype of …