Nitric Oxide and Peroxynitrite in Health and Disease

Abstract

The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.

IGF‐1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging

“…Second, the treatment of primary endothelial cells with IGF‐1 significantly attenuates cellular ROS generation (Csiszar et al ., 2008). Third, in the microcirculation, endothelium‐derived NO was shown to react with increased O 2 .− forming ONOO − , thus decreasing the bioavailability of NO (Csiszar et al ., 2002; Pacher et al ., 2007). The brains of IGF‐1‐deficient mice, similar to aged mice (Toth et al ., 2014a), exhibit an increased 3‐nitrotyrosine content (Fig.…”

Prevention of the development of heart failure with preserved ejection fraction by the phosphodiesterase‐5A inhibitor vardenafil in rats with type 2 diabetes

“…Several mechanisms have been described to play a decisive role in DM‐associated nitro‐oxidative stress such as the upregulation of NADPH‐oxidases and NO synthases 3. Moreover, in nitro‐oxidative stress peroxynitrite is generated when ROS directly reacts with NO thus it contributes to the decreased NO bioavailability 26. Peroxynitrite is a highly reactive molecule that directly deteriorates different cellular elements, enzymes, myofibrillar proteins, and DNA 26.…”

Asymmetric Dimethylarginine Limits the Efficacy of Simvastatin Activating Endothelial Nitric Oxide Synthase

“…eNOS can be activated by physiological and metabolic stimuli, such as shear stress and clinical therapeutic drugs, and result in NO production. The protective effects of NO on the cardiovascular system are well documented29, 30, 31; NO functionally inhibits platelet aggregation, leukocyte adhesion, and smooth muscle cell proliferation and maintains vascular tone, thereby maintaining cardiovascular homeostasis and preventing cardiovascular diseases 32, 33, 34. However, at the initial stage of several cardiovascular diseases, oxidative stress uncouples eNOS‐derived NO, thereby increasing ONOO‐ production, which deregulates eNOS activity and leads to disease progression 35, 36, 37, 38.…”