Endogenous peroxynitrite modulates PGHS-1–dependent thromboxane A 2 formation and aggregation in human platelets

Abstract

Aggregation of activated platelets is considerably mediated by the autocrine action of thromboxane A 2 (TxA 2) which is formed in a prostaglandin endoperoxide H 2 synthase-1 (PGHS-1 or COX-1)-dependent manner. The activity of PGHS-1 can be stimulated by peroxides, an effect termed “peroxide tone”, that renders PGHS-1 the key regulatory enzyme in the formation of TxA 2. Activated platelets release nitric oxide ( ·NO) and superoxide ( ·O 2 -) but their interactions with the prostanoid pathway have been controversially discussed in platelet physiology and pathophysiology. The current study demonstrates that endogenously formed peroxynitrite at nanomolar concentrations, originating from the interaction of ·NO and ·O 2 -, potently activated PGHS-1, which parallels TxA 2 formation and aggregation in human platelets. Inhibition of the endogenous formation of either ·NO or ·O 2 - resulted in a concentration-dependent decline of PGHS-1 activity, TxA 2 release, and aggregation. The concept of peroxynitrite as modulator of TxA 2 formation and aggregation explains the interaction of ·NO and ·O 2 - with the PGHS pathway and suggests a mechanism by which antioxidants can regulate PGHS-1-dependent platelet aggregation. This may provide a molecular explanation for the clinically observed hyperreactivity of platelets in high-risk patients and serve as a basis for novel therapeutic interventions.