[Frontiers in Bioscience 14, 4809-4814, January 1, 2009]

Role of peroxynitrite in the redox regulation of cell signal transduction pathways Lucas Liaudet1, Giuseppe Vassalli2, Pal Pacher3

1Department of Intensive Care Medicine, 2Service of Cardiology, University Medical Center and Faculty of Biology and Medicine, Lausanne, Switzerland, 3Section on Oxidative Stress Tissue Injury, Laboratory of Physiologic Studies, NIH/NIAA, Bethesda, MD, USA

TABLE OF CONTENTS

1. Abstract
2. Introduction: Formation, reactivity and chemical biology of peroxynitrite
3. Redox regulation of cell signalling by peroxynitrite
3.1. Tyrosine nitration and modulation of phosphotyrosine signalling
3.2. Peroxynitrite-mediated regulation of individual cell signalling pathways
3.2.1. Akt/Protein Kinase B
3.2.2. Mitogen-activated protein kinases
3.2.2.1. Extracellular signal-regulated protein kinase (ERK)
3.2.2.2. c-Jun NH2-terminal kinase (JNK)
3.2.2.3. p38 MAP kinase
3.2.3. Protein Kinase C
3.2.4. Nuclear Factor kappa B
3.2.5. Insulin signalling
3.2.6. Sympatho-adrenergic signalling
4. Conclusions and perspectives
5. Acknowledgments
6. References

1. ABSTRACT

Peroxynitrite is a potent oxidant and nitrating species formed from the reaction between the free radicals nitric oxide and superoxide. An excessive formation of peroxynitrite represents an important mechanism contributing to cell death and dysfunction in multiple cardiovascular pathologies, such as myocardial infarction, heart failure and atherosclerosis. Whereas initial works focused on direct oxidative biomolecular damage as the main route of peroxynitrite toxicity, more recent evidence, mainly obtained in vitro, indicates that peroxynitrite also behaves as a potent modulator of various cell signal transduction pathways. Due to its ability to nitrate tyrosine residues, peroxynitrite affects cellular processes dependent on tyrosine phosphorylation. Peroxynitrite also exerts complex effects on the activity of various kinases and phosphatases, resulting in the up- or downregulation of signalling cascades, in a concentration- and cell-dependent manner. Such roles of peroxynitrite in the redox regulation of key signalling pathways for cardiovascular homeostasis, including protein kinase B and C, the MAP kinases, Nuclear Factor Kappa B, as well as signalling dependent on insulin and the sympatho-adrenergic system are presented in detail in this review.