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

Endogenous peroxynitrite modulates PGHS-1–dependent thromboxane A2 formation and aggregation in human platelets

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SCHILDKNECHT, Stefan, Bernd VAN DER LOO, Klaus WEBER, Katja TIEFENTHALER, Andreas DAIBER, Markus Michael BACHSCHMID, 2008. Endogenous peroxynitrite modulates PGHS-1–dependent thromboxane A2 formation and aggregation in human platelets. In: Free radical biology & medicine. 45(4), pp. 512-520. ISSN 0891-5849. eISSN 1873-4596. Available under: doi: 10.1016/j.freeradbiomed.2008.04.042

@article{Schildknecht2008-08-15Endog-38559, title={Endogenous peroxynitrite modulates PGHS-1–dependent thromboxane A2 formation and aggregation in human platelets}, year={2008}, doi={10.1016/j.freeradbiomed.2008.04.042}, number={4}, volume={45}, issn={0891-5849}, journal={Free radical biology & medicine}, pages={512--520}, author={Schildknecht, Stefan and Van Der Loo, Bernd and Weber, Klaus and Tiefenthaler, Katja and Daiber, Andreas and Bachschmid, Markus Michael} }

2017-04-21T12:48:47Z Daiber, Andreas Daiber, Andreas Schildknecht, Stefan Aggregation of activated platelets is considerably mediated by the autocrine action of thromboxane A2 (TxA2) which is formed in a prostaglandin endoperoxide H2 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 TxA2. 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 *O2, potently activated PGHS-1, which parallels TxA2 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, TxA2 release, and aggregation. The concept of peroxynitrite as modulator of TxA2 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. 2017-04-21T12:48:47Z Endogenous peroxynitrite modulates PGHS-1–dependent thromboxane A<sub>2</sub> formation and aggregation in human platelets Schildknecht, Stefan Tiefenthaler, Katja Tiefenthaler, Katja 2008-08-15 Weber, Klaus eng Weber, Klaus Bachschmid, Markus Michael Van Der Loo, Bernd Van Der Loo, Bernd Bachschmid, Markus Michael

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