PEROXYNITRITE INACTIVATES PROSTACYCLIN SYNTHASE BY HEME–THIOLATE-CATALYZED TYROSINE NITRATION

Abstract

Previous work has shown a sensitive inhibition of prostacyclin synthase activity by peroxynitrite as well as by superoxide in the presence of NO donors. Neither superoxide nor NO alone nor decomposed peroxynitrite is effective. The inhibition of activity was paralleled by a nitration of a tyrosine residue and both could be prevented by a stable substrate analog. The same IC₅₀ value for peroxynitrite was also found for the cellular prostacyclin activity in endothelial and kidney mesangial cells, indicating that the antioxidant potential of the cell cannot prevent the inactivation. Aortic tissue shows a co-localization of prostacyclin synthase and nitrotyrosine staining after treatment of the tissue with 1 μM peroxynitrite. It can be speculated that this pathway of enzyme nitration is of pathophysiological significance.

Key Words :

• Superoxide
• Nitric oxide
• Cyochrome P450
• Endothelial cell