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Nitric Oxide Synthases: Regulation and Function

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 March 2019) | Viewed by 47278

Special Issue Editor

Special Issue Information

Dear Colleagues,

Nitric oxide (NO) is a bioactive gas in the body and plays a crucial role in maintaining the homeostasis of the cardiovascular system. It can be synthesized by endothelial nitric oxide synthase (eNOS), neuronal NO synthase (nNOS), and inducible NO synthase (iNOS), which convert arginine into citrulline and produce NO in several cell types. In addition to its key role in regulating the cardiovascular function, NO has been reported to be involved in the pathological processes of a variety of human diseases, including cardiovascular diseases, metabolic diseases, inflammatory diseases, cancer, and neurological diseases. Given the importance of NOSs in the pathophysiology of human diseases, these enzymes are considered potential therapeutic targets for the treatment of diverse human pathologies. The Special Issue entitled "Nitric Oxide Synthases: Regulation and Function" aims to provide a research platform for the collection of the latest review and original research articles covering all aspects of these enzymes.

Prof. Dr. Tzong-Shyuan Lee
Guest Editor

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Keywords

  • NOSs
  • nitric oxide synthases
  • isoforms
  • nitric oxide
  • endothelial cell
  • stem cell
  • cellular signaling
  • redox pathway
  • endothelial NOS
  • neuronal NOS
  • disease
  • cancer

Published Papers (8 papers)

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Research

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22 pages, 3195 KiB  
Article
Hyperglycaemia-Induced Downregulation in Expression of nNOS Intramural Neurons of the Small Intestine in the Pig
by Michał Bulc, Katarzyna Palus, Michał Dąbrowski and Jarosław Całka
Int. J. Mol. Sci. 2019, 20(7), 1681; https://doi.org/10.3390/ijms20071681 - 04 Apr 2019
Cited by 18 | Viewed by 2688
Abstract
Diabetic autonomic peripheral neuropathy (PN) involves a broad spectrum of organs. One of them is the gastrointestinal (GI) tract. The molecular mechanisms underlying the pathogenesis of digestive complications are not yet fully understood. Digestion is controlled by the central nervous system (CNS) and [...] Read more.
Diabetic autonomic peripheral neuropathy (PN) involves a broad spectrum of organs. One of them is the gastrointestinal (GI) tract. The molecular mechanisms underlying the pathogenesis of digestive complications are not yet fully understood. Digestion is controlled by the central nervous system (CNS) and the enteric nervous system (ENS) within the wall of the GI tract. Enteric neurons exert regulatory effects due to the many biologically active substances secreted and released by enteric nervous system (ENS) structures. These include nitric oxide (NO), produced by the neural nitric oxide synthase enzyme (nNOS). It is a very important inhibitory factor, necessary for smooth muscle relaxation. Moreover, it was noted that nitrergic innervation can undergo adaptive changes during pathological processes. Additionally, nitrergic neurons function may be regulated through the synthesis of other active neuropeptides. Therefore, in the present study, using the immunofluorescence technique, we first examined the influence of hyperglycemia on the NOS- containing neurons in the porcine small intestine and secondly the co-localization of nNOS with vasoactive intestinal polypeptide (VIP), galanin (GAL) and substance P (SP) in all plexuses studied. Following chronic hyperglycaemia, we observed a reduction in the number of the NOS-positive neurons in all intestinal segments studied, as well as an increased in investigated substances in nNOS positive neurons. This observation confirmed that diabetic hyperglycaemia can cause changes in the neurochemical characteristics of enteric neurons, which can lead to numerous disturbances in gastrointestinal tract functions. Moreover, can be the basis of an elaboration of these peptides analogues utilized as therapeutic agents in the treatment of GI complications. Full article
(This article belongs to the Special Issue Nitric Oxide Synthases: Regulation and Function)
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15 pages, 3182 KiB  
Article
Nitric Oxide Reverses the Position of the Heart during Embryonic Development
by Jamila H Siamwala, Pavitra Kumar, Vimal Veeriah, Ajit Muley, Saranya Rajendran, Salini Konikkat, Syamantak Majumder, Krishna Priya Mani and Suvro Chatterjee
Int. J. Mol. Sci. 2019, 20(5), 1157; https://doi.org/10.3390/ijms20051157 - 07 Mar 2019
Cited by 12 | Viewed by 3567
Abstract
Nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) plays crucial roles in cardiac homeostasis. Adult cardiomyocyte specific overexpression of eNOS confers protection against myocardial-reperfusion injury. However, the global effects of NO overexpression in developing cardiovascular system is still unclear. We hypothesized [...] Read more.
Nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) plays crucial roles in cardiac homeostasis. Adult cardiomyocyte specific overexpression of eNOS confers protection against myocardial-reperfusion injury. However, the global effects of NO overexpression in developing cardiovascular system is still unclear. We hypothesized that nitric oxide overexpression affects the early migration of cardiac progenitor cells, vasculogenesis and function in a chick embryo. Vehicle or nitric oxide donor DEAN (500 µM) were loaded exogenously through a small window on the broad side of freshly laid egg and embryonic development tracked by live video-microscopy. At Hamburg Hamilton (HH) stage 8, the cardiac progenitor cells (CPC) were isolated and cell migration analysed by Boyden Chamber. The vascular bed structure and heart beats were compared between vehicle and DEAN treated embryos. Finally, expression of developmental markers such as BMP4, Shh, Pitx2, Noggin were measured using reverse transcriptase PCR and in-situ hybridization. The results unexpectedly showed that exogenous addition of pharmacological NO between HH stage 7–8 resulted in embryos with situs inversus in 28 out of 100 embryos tested. Embryos treated with NO inhibitor cPTIO did not have situs inversus, however 10 embryos treated with L-arginine showed a situs inversus phenotype. N-acetyl cysteine addition in the presence of NO failed to rescue situs inversus phenotype. The heart beat is normal (120 beats/min) although the vascular bed pattern is altered. Migration of CPCs in DEAN treated embryos is reduced by 60% compared to vehicle. BMP4 protein expression increases on the left side of the embryo compared to vehicle control. The data suggests that the NO levels in the yolk are important in turning of the heart during embryonic development. High levels of NO may lead to situs inversus condition in avian embryo by impairing cardiac progenitor cell migration through the NO-BMP4-cGMP axis. Full article
(This article belongs to the Special Issue Nitric Oxide Synthases: Regulation and Function)
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14 pages, 4466 KiB  
Article
Protective Effects of Rhodiola Crenulata Extract on Hypoxia-Induced Endothelial Damage via Regulation of AMPK and ERK Pathways
by Pi-Kai Chang, I-Chuan Yen, Wei-Cheng Tsai, Tsu-Chung Chang and Shih-Yu Lee
Int. J. Mol. Sci. 2018, 19(8), 2286; https://doi.org/10.3390/ijms19082286 - 03 Aug 2018
Cited by 19 | Viewed by 8469
Abstract
Rhodiola crenulata root extract (RCE) has been shown to possess protective activities against hypoxia both in vitro and in vivo. However, the effects of RCE on response to hypoxia in the endothelium remain unclear. In this study, we aimed to examine the effects [...] Read more.
Rhodiola crenulata root extract (RCE) has been shown to possess protective activities against hypoxia both in vitro and in vivo. However, the effects of RCE on response to hypoxia in the endothelium remain unclear. In this study, we aimed to examine the effects of RCE in endothelial cells challenged with hypoxic exposure and to elucidate the underlying mechanisms. Human umbilical vein endothelial cells were pretreated with or without RCE and then exposed to hypoxia (1% O2) for 24 h. Cell viability, nitric oxide (NO) production, oxidative stress markers, as well as mechanistic readouts were studied. We found that hypoxia-induced cell death, impaired NO production, and oxidative stress. These responses were significantly attenuated by RCE treatment and were associated with the activation of AMP-activated kinase and extracellular signal-regulated kinase 1/2 signaling pathways. In summary, we showed that RCE protected endothelial cells from hypoxic insult and suggested that R. crenulata might be useful for the prevention of hypoxia-associated vascular dysfunction. Full article
(This article belongs to the Special Issue Nitric Oxide Synthases: Regulation and Function)
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Review

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10 pages, 1115 KiB  
Review
Nitrergic Enteric Neurons in Health and Disease—Focus on Animal Models
by Nikolett Bódi, Zita Szalai and Mária Bagyánszki
Int. J. Mol. Sci. 2019, 20(8), 2003; https://doi.org/10.3390/ijms20082003 - 24 Apr 2019
Cited by 32 | Viewed by 3710
Abstract
Nitrergic enteric neurons are key players of the descending inhibitory reflex of intestinal peristalsis, therefore loss or damage of these neurons can contribute to developing gastrointestinal motility disturbances suffered by patients worldwide. There is accumulating evidence that the vulnerability of nitrergic enteric neurons [...] Read more.
Nitrergic enteric neurons are key players of the descending inhibitory reflex of intestinal peristalsis, therefore loss or damage of these neurons can contribute to developing gastrointestinal motility disturbances suffered by patients worldwide. There is accumulating evidence that the vulnerability of nitrergic enteric neurons to neuropathy is strictly region-specific and that the two main enteric plexuses display different nitrergic neuronal damage. Alterations both in the proportion of the nitrergic subpopulation and in the total number of enteric neurons suggest that modification of the neurochemical character or neuronal death occurs in the investigated gut segments. This review aims to summarize the gastrointestinal region and/or plexus-dependent pathological changes in the number of nitric oxide synthase (NOS)-containing neurons, the NO release and the cellular and subcellular expression of different NOS isoforms. Additionally, some of the underlying mechanisms associated with the nitrergic pathway in the background of different diseases, e.g., type 1 diabetes, chronic alcoholism, intestinal inflammation or ischaemia, will be discussed. Full article
(This article belongs to the Special Issue Nitric Oxide Synthases: Regulation and Function)
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16 pages, 1970 KiB  
Review
The Potential Role of iNOS in Ovarian Cancer Progression and Chemoresistance
by Michal Kielbik, Izabela Szulc-Kielbik and Magdalena Klink
Int. J. Mol. Sci. 2019, 20(7), 1751; https://doi.org/10.3390/ijms20071751 - 09 Apr 2019
Cited by 40 | Viewed by 4445
Abstract
Inducible nitric oxide synthase (iNOS), the enzyme responsible for nitric oxide (NO) production, is not present in most cells under normal conditions. The expression of its mRNA, as well as its protein synthesis and full enzymatic activity, undergoes multilevel regulation including transcriptional and [...] Read more.
Inducible nitric oxide synthase (iNOS), the enzyme responsible for nitric oxide (NO) production, is not present in most cells under normal conditions. The expression of its mRNA, as well as its protein synthesis and full enzymatic activity, undergoes multilevel regulation including transcriptional and posttranscriptional mechanisms, the availability of iNOS substrate and cofactors and oxygen tension. However, in various malignant diseases, such as ovarian cancer, the intracellular mechanisms controlling iNOS are dysregulated, resulting in the permanent induction of iNOS expression and activation. The present review summarizes the multistaged processes occurring in normal cells that promote NO synthesis and focuses on factors regulating iNOS expression in ovarian cancer. The possible involvement of iNOS in the chemoresistance of ovarian cancer and its potential as a prognostic/predictive factor in the course of disease development are also reviewed. According to the available yet limited data, it is difficult to draw unequivocal conclusions on the pros and cons of iNOS in ovarian cancer. Most clinical data support the hypothesis that high levels of iNOS expression in ovarian tumors are associated with a greater risk of disease relapse and patient death. However, in vitro studies with various ovarian cancer cell lines indicate a correlation between a high level of iNOS expression and sensitivity to cisplatin. Full article
(This article belongs to the Special Issue Nitric Oxide Synthases: Regulation and Function)
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16 pages, 1038 KiB  
Review
Regulation of Nitric Oxide Production in the Developmental Programming of Hypertension and Kidney Disease
by Chien-Ning Hsu and You-Lin Tain
Int. J. Mol. Sci. 2019, 20(3), 681; https://doi.org/10.3390/ijms20030681 - 05 Feb 2019
Cited by 71 | Viewed by 4928
Abstract
Development of the kidney can be altered in response to adverse environments leading to renal programming and increased vulnerability to the development of hypertension and kidney disease in adulthood. By contrast, reprogramming is a strategy shifting therapeutic intervention from adulthood to early life [...] Read more.
Development of the kidney can be altered in response to adverse environments leading to renal programming and increased vulnerability to the development of hypertension and kidney disease in adulthood. By contrast, reprogramming is a strategy shifting therapeutic intervention from adulthood to early life to reverse the programming processes. Nitric oxide (NO) is a key mediator of renal physiology and blood pressure regulation. NO deficiency is a common mechanism underlying renal programming, while early-life NO-targeting interventions may serve as reprogramming strategies to prevent the development of hypertension and kidney disease. This review will first summarize the regulation of NO in the kidney. We also address human and animal data supporting the link between NO system and developmental programming of hypertension and kidney disease. This will be followed by the links between NO deficiency and the common mechanisms of renal programming, including the oxidative stress, renin–angiotensin system, nutrient-sensing signals, and sex differences. Recent data from animal studies have suggested that interventions targeting the NO pathway could be reprogramming strategies to prevent the development of hypertension and kidney disease. Further clinical studies are required to bridge the gap between animal models and clinical trials in order to develop ideal NO-targeting reprogramming strategies and to be able to have a lifelong impact, with profound savings in the global burden of hypertension and kidney disease. Full article
(This article belongs to the Special Issue Nitric Oxide Synthases: Regulation and Function)
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29 pages, 3100 KiB  
Review
Nitric Oxide and the Neuroendocrine Control of the Osmotic Stress Response in Teleosts
by Carla Cioni, Elisa Angiulli and Mattia Toni
Int. J. Mol. Sci. 2019, 20(3), 489; https://doi.org/10.3390/ijms20030489 - 23 Jan 2019
Cited by 12 | Viewed by 3841
Abstract
The involvement of nitric oxide (NO) in the modulation of teleost osmoresponsive circuits is suggested by the facts that NO synthase enzymes are expressed in the neurosecretory systems and may be regulated by osmotic stimuli. The present paper is an overview on the [...] Read more.
The involvement of nitric oxide (NO) in the modulation of teleost osmoresponsive circuits is suggested by the facts that NO synthase enzymes are expressed in the neurosecretory systems and may be regulated by osmotic stimuli. The present paper is an overview on the research suggesting a role for NO in the central modulation of hormone release in the hypothalamo-neurohypophysial and the caudal neurosecretory systems of teleosts during the osmotic stress response. Active NOS enzymes are constitutively expressed by the magnocellular and parvocellular hypophysiotropic neurons and the caudal neurosecretory neurons of teleosts. Moreover, their expression may be regulated in response to the osmotic challenge. Available data suggests that the regulatory role of NO appeared early during vertebrate phylogeny and the neuroendocrine modulation by NO is conservative. Nonetheless, NO seems to have opposite effects in fish compared to mammals. Indeed, NO exerts excitatory effects on the electrical activity of the caudal neurosecretory neurons, influencing the amount of peptides released from the urophysis, while it inhibits hormone release from the magnocellular neurons in mammals. Full article
(This article belongs to the Special Issue Nitric Oxide Synthases: Regulation and Function)
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13 pages, 540 KiB  
Review
Regulation of iNOS on Immune Cells and Its Role in Diseases
by Qingjie Xue, Yingchun Yan, Ruihua Zhang and Huabao Xiong
Int. J. Mol. Sci. 2018, 19(12), 3805; https://doi.org/10.3390/ijms19123805 - 29 Nov 2018
Cited by 253 | Viewed by 14766
Abstract
In recent years, there have been many studies on the function of nitric oxide synthase (NOS) in experimental animals and humans. This review analyzes and explores the relationship between inducible nitric oxide synthase (iNOS) and T cells, macrophages, and dendritic cell et al. [...] Read more.
In recent years, there have been many studies on the function of nitric oxide synthase (NOS) in experimental animals and humans. This review analyzes and explores the relationship between inducible nitric oxide synthase (iNOS) and T cells, macrophages, and dendritic cell et al. differentiation using data based on laboratory research, highlighting recent NOS laboratory research. Our insights into research prospects and directions are also presented. Full article
(This article belongs to the Special Issue Nitric Oxide Synthases: Regulation and Function)
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