Nitric Oxide in Cell Survival: A Janus Molecule

Abstract

Nitric oxide (NO), plays multiple roles in the nervous system. In addition to regulating proliferation, survival and differentiation of neurons, NO is involved in synaptic activity, neural plasticity, and memory function. Nitric oxide promotes survival and differentiation of neural cells and exerts long-lasting effects through regulation of transcription factors and modulation of gene expression. Signaling by reactive nitrogen species is carried out mainly by targeted modifications of critical cysteine residues in proteins, including S-nitrosylation and S-oxidation, as well as by lipid nitration. NO and other reactive nitrogen species are also involved in neuroinflammation and neurodegeneration, such as in Alzheimer disease, amyotrophic lateral sclerosis, Parkinson disease, multiple sclerosis, Friedreich ataxia, and Huntington disease. Susceptibility to NO and peroxynitrite exposure may depend on factors such as the intracellular reduced glutathione and cellular stress resistance signaling pathways. Thus, neurons, in contrast to astrocytes, appear particularly vulnerable to the effects of nitrosative stress. This article reviews the current understanding of the cytotoxic versus cytoprotective effects of NO in the central nervous system, highlighting the Janus-faced properties of this small molecule. The significance of NO in redox signaling and modulation of the adaptive cellular stress responses and its exciting future perspectives also are discussed.

Redox regulation of cellular stress response in multiple sclerosis

“…This latter is then reduced by biliverdin reductase (BVR) into bilirubin (BR), a linear tetrapyrrole with antioxidant properties; very recently, BR has been shown to effectively counteract also nitrosative stress, due to its ability to bind and inactivate NO and RNS [14,17]. The constitutive isoform of heme oxygenase is HO-2 [28,29].…”

“…This finding is consistent with evidence suggesting that the HO-1 gene is redox regulated and, similar to other antioxidant enzymes [50], this occurs because it contains in its promoter region the antioxidant responsive element (ARE). Therefore, the HO-1 gene undergoes a redox sensitive modulation by transcription factors recognizing specific binding sites within the promoter and distal enhancer regions of the HO-1 gene [14,15]. In addition, heme oxygenase-1 is rapidly upregulated by oxidative and nitrosative stresses, as well as by glutathione depletion [51].…”

“…The adaptation and survival of cells and organisms requires the ability to sense proteotoxic insults and to coordinate protective cellular stress response pathways and chaperone networks related to protein quality control [13]. Despite the abundance and apparent capacity of chaperones and other components of homeostasis to restore folding equilibrium, brain cells appears poorly adapted for chronic proteotoxic stress which increases in neurodegenerative diseases such as MS [14]. In these conditions, a decline in biosynthetic and repair activities that compromises the integrity of the proteome is strongly influenced by protective genes called ''vitagenes'' that control aging, thus linking stress and protein homeostasis with the health antidegenerative mechanisms [15].…”

“…In the CNS, Hsps synthesis occurs after hyperthermia, alterations in the intracellular redox environment, exposure to heavy metals, amino acid analogs or cytotoxic drugs [15]. While prolonged exposure to conditions of extreme stress is detrimental and can induce cell death, Hsps synthesis can result in stress tolerance and cytoprotection in various metabolic diseases and injuries, including hypoxia, stroke, epilepsy, cell and tissue trauma, neurodegenerative disease and aging [14]. Sirtuins (SIRTs) represent a highly conserved gene family encoding NAD+-dependent deacetylases, originally found to deacetylate histones leading to increased DNA stability and prolonged survival in yeast and higher organisms, including mammals.…”

FoxO1 and SIRT1 Regulate β-Cell Responses to Nitric Oxide

“…At points in which ␤-cells no longer have the capacity to recover from this damage, cytokine-mediated ␤-cell death shifts to an apoptotic process that is associated with irreversible DNA damage and caspase activation (14). Similar to what has been observed in ␤-cells, nitric oxide has been implicated in the induction of both necrosis and apoptosis of multiple cell types (27)(28)(29).Although nitric oxide is a known activator of p53 (30, 31), we recently observed that the repair of nitric oxide-damaged DNA in ␤-cells occurs by a p53-independent but GADD45␣-dependent process (32). A number of studies have shown that GADD45␣ expression is regulated by p53 (33).…”