Signaling and stress: The redox landscape in NOS2 biology

Abstract

Nitric oxide (NO) has a highly diverse range of biological functions from physiological signaling and maintenance of homeostasis to serving as an effector molecule in the immune system. Many of the dichotomous effects of NO and derivative reactive nitrogen species (RNS) can be explained by invoking precise interactions with different targets as a result of concentration and temporal constraints. Endogenous concentrations of NO span five orders of magnitude, with levels near the high picomolar range typically occurring in short bursts as compared to sustained production of low micromolar levels of NO during immune response. This article provides an overview of the redox landscape as it relates to increasing NO concentrations, which incrementally govern physiological signaling, nitrosative signaling and nitrosative stress-related signaling. Physiological signaling by NO primarily occurs upon interaction with the heme protein soluble guanylyl cyclase. As NO concentrations rise, interactions with nonheme iron complexes as well as indirect modification of thiols can stimulate additional signaling processes. At the highest levels of NO, production of a broader range of RNS, which subsequently interact with more diverse targets, can lead to chemical stress. However, even under such conditions, there is evidence that stress-related signaling mechanisms are triggered to protect cells or even resolve the stress. This review therefore also addresses the fundamental reactions and kinetics that initiate signaling through NO-dependent pathways, including the chemistry of RNS and their molecular targets.

Oxidative Stress: Noxious but Also Vital

“…Nitric oxide is a membrane permeable free radical that participates in a multiple process in the cells as signaling molecule, but also can contribute in cell oxidative damage. Its effect depends on NO levels and localization in the cell microenvironment [35,36]. When nitric oxide is present in environment, as in mitochondrial matrix, the reaction of this free radical with superoxide can form others RNS, as peroxynitrite.…”

“…Mitochondria and reactive species: physiological level, oxidative stress, and its implications ROS and RNS are normally produced in metabolism and have an important role as signaling molecules regulating diverse physiological cell events, as cell signaling, metabolism and regulation of transcription factors [35,[38][39][40][41][42].…”

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

“…The inhibition of TSP1 expression at 1000 lM DETA/NO coincided with increased phosphorylation of p53 at Ser 15 and increased expression of MAP kinase phosphatase-1 (MKP1/DUSP1). Oxidative stress induces MKP1/DUSP1 expression in a p53-dependent manner (146), and both alterations are likely mediated by reactive nitrogen species (RNS) rather than directly by NO (272). MKP1 levels varied inversely with ERK phosphorylation across the NO dose response, suggesting that MKP1 inhibits the ERK-dependent regulation of TSP1 expression.…”

Modulation of the Anti-Tumor Efficacy of Photodynamic Therapy by Nitric Oxide

“…Activated nNOS and eNOS, which are often categorized together as constitutive NOS (cNOS), generate NO at low levels (nanomolar range) for less than a minute, whereas activated iNOS generates NO at much higher levels (micromolar range) for hours or even days [4,6]. NOS-derived NO is highly pleiotropic in terms of biological action, playing a role in many different physiological and pathophysiological processes, ranging from vasodilation (eNOS), neurotransmission (nNOS), and antimicrobial activity (iNOS) on the one hand, to chronic inflammation, tumor initiation, and tumor progression on the other, the last three typically associated with iNOS [4,5,6,7]. …”