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

Schildknecht, Stefan and van der Loo, Bernd and Weber, Klaus and Tiefenthaler, Katja and Daiber, Andreas and Bachschmid, Markus Michael (2008) Endogenous peroxynitrite modulates PGHS-1-dependent thromboxane A(2) formation and aggregation in human platelets. FREE RADICAL BIOLOGY AND MEDICINE, 45 (4). pp. 512-520.

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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 peroxymtrite 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. (c) 2008 Elsevier Inc. All rights reserved.

Item Type:Article
Uncontrolled Keywords:prostaglandin endoperoxide synthase; peroxynitrite; nitric oxide; superoxide; thromboxane A(2); platelets; peroxide tone
Subjects:Biomedical Science > Nanomedicine
ID Code:719
Deposited By:SPI
Deposited On:21 Jan 2009 12:18
Last Modified:21 Jan 2009 12:18

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