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Vascular Redox Signaling, Redox Switches in Endothelial Nitric Oxide Synthase (eNOS Uncoupling), and Endothelial Dysfunction

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Abstract

Many diseases and drug-induced complications are associated with – or even caused by – an imbalance between the formation of reactive oxygen and nitrogen species (RONS) and antioxidant enzymes catalyzing the breakdown of these harmful oxidants. According to the “kindling radical” hypothesis, initial formation of RONS may trigger the activation of additional sources of RONS in certain pathological conditions. This chapter will focus on the uncoupling of endothelial nitric oxide synthase (eNOS) by RONS and will focus on the different “redox switches” that are involved in the uncoupling process of eNOS. The oxidative depletion of tetrahydrobiopterin (BH4), oxidative disruption of the zinc-sulfur cluster in the binding region of the dimeric eNOS complex, and S-glutathionylation of the eNOS reductase domain will be discussed as potential pathways for eNOS uncoupling. In addition, protein kinase C (PKC)-dependent phosphorylation of threonine 495 in the reductase domain, protein tyrosine kinase-2 (PYK-2)-dependent phosphorylation of tyrosine 657 in the reductase domain, RONS-triggered increases in levels of asymmetric dimethylarginine (ADMA), and l-arginine depletion will be highlighted as alternative reasons for dysfunctional eNOS. Finally, the clinical perspectives of eNOS uncoupling (and dysfunction) for cardiovascular disease are presented.

Keywords

Mitochondria NADPH oxidase Nitric oxide synthase uncoupling Oxidative stress Peroxynitrite Superoxide Xanthine oxidase 
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Notes

Acknowledgments

We thank Margot Neuser and Thilo Weckmüller for graphical assistance. The technical assistance of Jörg Schreiner and Angelica Karpi during our ongoing studies in the last years is gratefully acknowledged. The present work was supported by generous financial support by the Johannes Gutenberg University and Medical Center Mainz (MAIFOR and Forschungsfonds grants to A.D.).

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  1. 1.2nd Medical Clinic, Department of CardiologyMedical Center of the Johannes Gutenberg UniversityMainzGermany

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