Inducible nitric oxide synthase: Good or bad? Lind, Maggie; Hayes, Alan; Caprnda, Martin ...
Biomedicine & pharmacotherapy,
September 2017, 2017-Sep, 2017-09-00, 20170901, Letnik:
93
Journal Article
Recenzirano
Nitric oxide synthases (NOS) are a family of isoforms responsible for the synthesis of the potent dilator nitric oxide (NO). Expression of inducible NOS (iNOS) occurs in conditions of inflammation, ...and produces large amounts of NO. In pathological conditions iNOS is regarded as a harmful enzyme and is proposed to be a major contributor to diseases of the cardiovascular system such as atherosclerosis. In this review, we address the notion that iNOS is a detrimental enzyme in disease and discuss its potentially beneficial roles. Additionally, we describe other molecules associated with iNOS in diseases such as atherosclerosis, and current research on therapeutic inhibitors tested to reduced pathology associated with cardiovascular diseases (CVD).
Nitric oxide (NO) plays an important and diverse signalling role in the cardiovascular system, contributing to the regulation of vascular tone, endothelial function, myocardial function, haemostasis, ...and thrombosis, amongst many other roles. NO is synthesised through the nitric oxide synthase (NOS)-dependent L-arginine-NO pathway, as well as the nitrate-nitrite-NO pathway. The three isoforms of NOS, namely neuronal (NOS1), inducible (NOS2), and endothelial (NOS3), have different localisation and functions in the human body, and are consequently thought to have differing pathophysiological roles. Furthermore, as we continue to develop a deepened understanding of the different roles of NOS isoforms in disease, the possibility of therapeutically modulating NOS activity has emerged. Indeed, impaired (or dysfunctional), as well as overactive (or dysregulated) NOS activity are attractive therapeutic targets in cardiovascular disease. This review aims to describe recent advances in elucidating the physiological role of NOS isoforms within the cardiovascular system, as well as mechanisms of dysfunctional and dysregulated NOS in cardiovascular disease. We then discuss the modulation of NO and NOS activity as a target in the development of novel cardiovascular therapeutics.
The 1998 Nobel Prize in Medicine and Physiology for the discovery of nitric oxide, a nitrogen containing reactive oxygen species (also termed reactive nitrogen or reactive nitrogen/oxygen species) ...stirred great hopes. Clinical applications, however, have so far pertained exclusively to the downstream signaling of cGMP enhancing drugs such as phosphodiesterase inhibitors and soluble guanylate cyclase stimulators. All clinical attempts, so far, to inhibit NOS have failed even though preclinical models were strikingly positive and clinical biomarkers correlated perfectly. This rather casts doubt on our current way of target identification in drug discovery in general and our way of patient stratification based on correlating but not causal biomarkers or symptoms. The opposite, NO donors, nitrite and enhancing NO synthesis by eNOS/NOS3 recoupling in situations of NO deficiency, are rapidly declining in clinical relevance or hold promise but need yet to enter formal therapeutic guidelines, respectively. Nevertheless, NOS inhibition in situations of NO overproduction often jointly with enhanced superoxide (or hydrogen peroxide production) still holds promise, but most likely only in acute conditions such as neurotrauma (Stover et al., J Neurotrauma 31(19):1599-1606, 2014) and stroke (Kleinschnitz et al., J Cereb Blood Flow Metab 1508-1512, 2016; Casas et al., Proc Natl Acad Sci U S A 116(14):7129-7136, 2019). Conversely, in chronic conditions, long-term inhibition of NOS might be too risky because of off-target effects on eNOS/NOS3 in particular for patients with cardiovascular risks or metabolic and renal diseases. Nitric oxide synthases (NOS) and their role in health (green) and disease (red). Only neuronal/type 1 NOS (NOS1) has a high degree of clinical validation and is in late stage development for traumatic brain injury, followed by a phase II safety/efficacy trial in ischemic stroke. The pathophysiology of NOS1 (Kleinschnitz et al., J Cereb Blood Flow Metab 1508-1512, 2016) is likely to be related to parallel superoxide or hydrogen peroxide formation (Kleinschnitz et al., J Cereb Blood Flow Metab 1508-1512, 2016; Casas et al., Proc Natl Acad Sci U S A 114(46):12315-12320, 2017; Casas et al., Proc Natl Acad Sci U S A 116(14):7129-7136, 2019) leading to peroxynitrite and protein nitration, etc. Endothelial/type 3 NOS (NOS3) is considered protective only and its inhibition should be avoided. The preclinical evidence for a role of high-output inducible/type 2 NOS (NOS2) isoform in sepsis, asthma, rheumatic arthritis, etc. was high, but all clinical development trials in these indications were neutral despite target engagement being validated. This casts doubt on the role of NOS2 in humans in health and disease (hence the neutral, black coloring).
Here, we show that extracorporeal shock waves (ESW), at a low energy density value, quickly increase neuronal nitric oxide synthase (nNOS) activity and basal nitric oxide (NO) production in the rat ...glioma cell line C6. In addition, the treatment of C6 cells with ESW reverts the decrease of nNOS activity and NO production induced by a mixture of lipopolysaccharides (LPS), interferon-γ (IFN-γ) plus tumour necrosis factor-α (TNF-α). Finally, ESW treatment efficiently downregulates NF-κB activation and NF-κB-dependent gene expression, including inducible NOS and TNF-α. The present report suggests a possible molecular mechanism of the anti-inflammatory action of ESW treatment.
Ischemic stroke (IS) is a life-threatening disease worldwide. Nitric oxide (NO) derived from l-arginine catalyzed by NO synthase (NOS) is closely associated with IS. Three isomers of NOS (nNOS, eNOS ...and iNOS) produce different concentrations of NO, resulting in quite unlike effects during IS. Of them, n/iNOSs generate high levels of NO, detrimental to brain by causing nerve cell apoptosis and/or necrosis, whereas eNOS releases small amounts of NO, beneficial to the brain via increasing cerebral blood flow and improving nerve function. As a result, a large variety of NO regulators (NO donors or n/iNOS inhibitors) have been developed for fighting IS. Regrettably, up to now, no review systematically introduces the progresses in this area. This article first outlines dynamic variation rule of NOS/NO in IS, subsequently highlights advances in NO regulators against IS, and finally presents perspectives based on concentration-, site- and timing-effects of NO production to promote this field forward.
Adenocarcinoma not otherwise specified (NOS) is a malignant salivary gland tumor without the histological characteristics of other salivary gland tumors. It rarely occurs in the small salivary glands ...and development in the molar glands is extremely rare. We report a case of adenocarcinoma NOS occurring in the retromolar pad. The patient was a 75-year-old woman with a protrusive 10 × 15 mm mass in the retromolar region. The lesion was elastic soft and had an irregular surface. Biopsy resulted in a histopathological diagnosis of adenocarcinoma NOS. No regional or distant metastasis was observed in imaging. The tumor was successfully resected under general anesthesia. The postoperative course was uneventful and there has been no recurrence or metastasis seven years after the surgery.
Abstract Background Genome-wide association studies have not revealed any risk-conferring common genetic variants in Tourette syndrome (TS), requiring the adoption of alternative approaches to ...investigate the pathophysiology of this disorder. Methods We obtained the basal ganglia transcriptome by RNA sequencing in the caudate and putamen of nine TS and nine matched normal control subjects. Results We found 309 downregulated and 822 upregulated genes in the caudate and putamen (striatum) of TS individuals. Using data-driven gene network analysis, we identified 17 gene coexpression modules associated with TS. The top-scoring downregulated module in TS was enriched in striatal interneuron transcripts, which was confirmed by decreased numbers of cholinergic and gamma-aminobutyric acidergic interneurons by immunohistochemistry in the same regions. The top-scoring upregulated module was enriched in immune-related genes, consistent with activation of microglia in patients’ striatum. Genes implicated by copy number variants in TS were enriched in the interneuron module, as well as in a protocadherin module. Module clustering revealed that the interneuron module was correlated with a neuronal metabolism module. Conclusions Convergence of differential expression, network analyses, and module clustering, together with copy number variants implicated in TS, strongly implicates disrupted interneuron signaling in the pathophysiology of severe TS and suggests that metabolic alterations may be linked to their death or dysfunction.
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