scholarly journals Subcellular targeting and trafficking of nitric oxide synthases

2006 ◽  
Vol 396 (3) ◽  
pp. 401-409 ◽  
Author(s):  
Stefanie Oess ◽  
Ann Icking ◽  
David Fulton ◽  
Roland Govers ◽  
Werner Müller-Esterl
Keyword(s):  
Nitric Oxide ◽  
Molecular Mechanisms ◽  
No Production ◽  
Subcellular Targeting ◽  
Post Translational Modifications ◽  
Intracellular Targeting ◽  
Highly Active ◽  
Signalling Molecule ◽  
Close Proximity ◽  
And Function

Unlike most other endogenous messengers that are deposited in vesicles, processed on demand and/or secreted in a regulated fashion, NO (nitric oxide) is a highly active molecule that readily diffuses through cell membranes and thus cannot be stored inside the producing cell. Rather, its signalling capacity must be controlled at the levels of biosynthesis and local availability. The importance of temporal and spatial control of NO production is highlighted by the finding that differential localization of NO synthases in cardiomyocytes translates into distinct effects of NO in the heart. Thus NO synthases belong to the most tightly controlled enzymes, being regulated at transcriptional and translational levels, through co- and post-translational modifications, by substrate availability and not least via specific sorting to subcellular compartments, where they are in close proximity to their target proteins. Considerable efforts have been made to elucidate the molecular mechanisms that underlie the intracellular targeting and trafficking of NO synthases, to ultimately understand the cellular pathways controlling the formation and function of this powerful signalling molecule. In the present review, we discuss the mechanisms and triggers for subcellular routing and dynamic redistribution of NO synthases and the ensuing consequences for NO production and action.

The Signaling Pathways in Nitric Oxide Production by Neutrophils Exposed to N-nitrosodimethylamine

2018 ◽  
Vol 16 (2) ◽  
pp. 194-199
Author(s):  
Wioletta Ratajczak-Wrona ◽  
Ewa Jablonska
Keyword(s):  
Nitric Oxide ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Polymorphonuclear Neutrophils ◽  
Microbial Pathogens ◽  
Human Neutrophils ◽  
No Production ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

Background: Polymorphonuclear neutrophils (PMNs) play a crucial role in the innate immune system’s response to microbial pathogens through the release of reactive nitrogen species, including Nitric Oxide (NO). </P><P> Methods: In neutrophils, NO is produced by the inducible Nitric Oxide Synthase (iNOS), which is regulated by various signaling pathways and transcription factors. N-nitrosodimethylamine (NDMA), a potential human carcinogen, affects immune cells. NDMA plays a major part in the growing incidence of cancers. Thanks to the increasing knowledge on the toxicological role of NDMA, the environmental factors that condition the exposure to this compound, especially its precursors- nitrates arouse wide concern. Results: In this article, we present a detailed summary of the molecular mechanisms of NDMA’s effect on the iNOS-dependent NO production in human neutrophils. Conclusion: This research contributes to a more complete understanding of the mechanisms that explain the changes that occur during nonspecific cellular responses to NDMA toxicity.

Nitric oxide synthesis by rat pleural mesothelial cells: induction by cytokines and lipopolysaccharide

1993 ◽  
Vol 265 (2) ◽  
pp. L110-L116 ◽  
Author(s):  
M. W. Owens ◽  
M. B. Grisham
Keyword(s):  
Nitric Oxide ◽  
Mononuclear Cells ◽  
Interleukin 1 ◽  
Mesothelial Cells ◽  
No Production ◽  
Nitrate Accumulation ◽  
Pleural Mesothelial Cells ◽  
Nitrate Production ◽  
Close Proximity ◽  
Nitrite Nitrate

The close proximity of pleural mesothelial cells (PMC) and mononuclear cells during pleural inflammation suggests that leukocyte-derived products (e.g., cytokines) may play an important role in modulating PMC function. The purpose of this study was to determine whether certain cytokines and bacterial products induce PMC to produce nitric oxide (NO). Confluent monolayers of rat PMC were exposed to tumor necrosis factor (TNF), interleukin-1 beta (IL-1), gamma-interferon (IFN), or lipopolysaccharide (LPS) individually and in various double and triple combinations for 6–72 h. Concentrations of nitrite and nitrate were quantified and used as indirect indices of NO production. Nitrite/nitrate accumulation was maximal at 72 h, with most of the increase occurring from 48 to 72 h. Maximal nitrite/nitrate production was observed with triple combinations with the combination of LPS, IL-1, and TNF giving the highest concentration (137.4 +/- 2.8 microM). Nitrite/nitrate production was significantly inhibited by NG-nitro-L-arginine methyl ester, suggesting that nitrite and nitrate were derived from the L-arginine-dependent formation of NO. These data indicate that PMC can be induced to produce large amounts of NO in response to specific combinations of proinflammatory cytokines and LPS.

scholarly journals Smoking-Induced Inhibition of Number and Activity of Endothelial Progenitor Cells and Nitric Oxide in Males Were Reversed by Estradiol in Premenopausal Females

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Yijia Shao ◽  
Liang Luo ◽  
Zi Ren ◽  
Jiayi Guo ◽  
Xingxing Xiao ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cigarette Smoking ◽  
Premenopausal Women ◽  
Cross Sectional Study ◽  
Favorable Effect ◽  
No Production ◽  
Vascular Protection ◽  
Cross Sectional ◽  
And Function ◽  
Flow Mediated Vasodilation

Objectives. The number and activity of circulating EPCs were enhanced in premenopausal women contrast to postmenopausal females and age-matched males. Here, we investigated whether this favorable effect exists in premenopausal women and age-matched men with cigarette smoking. Methods. In a cross-sectional study, the number and activity of circulating EPCs and nitric oxide production (NO) as well as flow-mediated vasodilation (FMD) in both premenopausal women and age-matched men with or without cigarette smoking were studied. Results. Compared with age-matched men with or without smoking, the number and function of circulating EPCs as well as NO level in premenopausal women were obviously higher than that in the former and not affected by smoking. The number and function of circulating EPCs as well as NO level in male smokers were shown to be the most strongly inhibited. Furthermore, there was significant correlation between EPC number and activity, plasma NO level, and NO secretion by EPCs and FMD. Conclusions. Estradiol was deemed to play an important role in enhancing the number and activity of EPCs and NO production in premenopausal women even when affected by smoking, which may be the important mechanisms underlying vascular protection of estradiol in premenopausal women, but not in age-matched men.

Nitric oxide augments fetal pulmonary artery endothelial cell angiogenesis in vitro

2006 ◽  
Vol 290 (6) ◽  
pp. L1111-L1116 ◽  
Author(s):  
Vivek Balasubramaniam ◽  
Anne M. Maxey ◽  
Brian W. Fouty ◽  
Steven H. Abman
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cell ◽  
Oxygen Tension ◽  
Growth And Development ◽  
Tube Formation ◽  
No Production ◽  
Low Oxygen ◽  
Low Oxygen Tension ◽  
And Function ◽  
Pulmonary Artery Endothelial Cell

Growth and development of the lung normally occur in the low oxygen environment of the fetus. The role of this low oxygen environment on fetal lung endothelial cell growth and function is unknown. We hypothesized that low oxygen tension during fetal life enhances pulmonary artery endothelial cell (PAEC) growth and function and that nitric oxide (NO) production modulates fetal PAEC responses to low oxygen tension. To test this hypothesis, we compared the effects of fetal (3%) and room air (RA) oxygen tension on fetal PAEC growth, proliferation, tube formation, and migration in the presence and absence of the NO synthase (NOS) inhibitor Nω-nitro-l-arginine (LNA), and an NO donor, S-nitroso- N-acetylpenicillamine (SNAP). Compared with fetal PAEC grown in RA, 3% O2 increased tube formation by over twofold ( P < 0.01). LNA treatment reduced tube formation in 3% O2 but had no affect on tube formation in RA. Treatment with SNAP increased tube formation during RA exposure to levels observed in 3% O2. Exposure to 3% O2 for 48 h attenuated cell number (by 56%), and treatment with LNA reduced PAEC growth by 44% in both RA and 3% O2. We conclude that low oxygen tension enhances fetal PAEC tube formation and that NO is essential for normal PAEC growth, migration, and tube formation. Furthermore, we conclude that in fetal cells exposed to the relative hyperoxia of RA, 21% O2, NO overcomes the inhibitory effects of the increased oxygen, allowing normal PAEC angiogenesis and branching. We speculate that NO production maintains intrauterine lung vascular growth and development during exposure to low O2 in the normal fetus. We further speculate that NO is essential for pulmonary angiogenesis in fetal animal exposed to increased oxygen tension of RA and that impaired endothelial NO production may contribute to the abnormalities of angiogenesis see in infants with bronchopulmonary dysplasia.

Nitric oxide stimulates myoglobin gene and protein expression in vascular smooth muscle

2009 ◽  
Vol 423 (2) ◽  
pp. 169-177 ◽  
Author(s):  
Benjamin S. Rayner ◽  
Susan Hua ◽  
Tharani Sabaretnam ◽  
Paul K. Witting
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Cell Viability ◽  
Transcriptional Activation ◽  
Cell Signalling ◽  
No Production ◽  
Parallel Increase ◽  
Signalling Molecule ◽  
Gene And Protein Expression

Mb (myoglobin) is a haemoprotein present in cardiac, skeletal and smooth muscle and is primarily responsible for the storage and ‘facilitated transfer’ of molecular oxygen from the cell membrane to mitochondria. Also, Mb plays a role in regulating •NO (nitric oxide) homoeostasis through (i) binding •NO (Mb–NO complex); (ii) oxidation of •NO to nitrate; and (iii) formation of vasoactive S-nitroso-Mb [Rayner, B.S., Wu, B.-J., Raftery, M., Stocker, R. and Witting, P.K. (2005) J. Biol. Chem. 280, 9985–9993]. Pathological •NO concentrations affect mitochondrial function and decrease cell viability through inducing apoptosis. Treatment of cultured rat VSMCs (vascular smooth muscle cells) with cumulative doses (0.1, 1 or 10 μM) of •NO from the donors diethylamineNONOate or spermineNONOate (N-[2-aminoethyl]-N-[2-hydroxy-3-nitrosohydrazine]-1,2-ethelenediamine) yielded a time-dependent increase in Mb gene expression. Concomitant transcriptional activation increased the concentration of Mb within cultured rat or primary human VSMCs as judged by Western blot analysis and indirect immunofluorescence microscopy. Cell viability did not decrease in these cells at the •NO doses tested. Importantly, sub-culturing isolated rat aortic segments for 7 days in the presence of L-arginine at 37 °C stimulated •NO production with a parallel increase in Mb in the underlying VSMCs. Overall, exposure of VSMCs (either in cell culture or intact vessels) to pathological •NO promotes an up-regulation of the Mb gene and protein, suggesting a feedback relationship between •NO and Mb that regulates the concentration of the potent cell signalling molecule in the vessel wall, similar to the role haemoglobin plays in the vessel lumen.

scholarly journals Lymphatic Muscle Cells Contribute to Dysfunction of the Synovial Lymphatic System in Inflammatory Arthritis in Mice

2020 ◽  
Author(s):  
Qianqian Liang ◽  
Li Zhang ◽  
Hao Xu ◽  
Jinlong Li ◽  
Yan Chen ◽  
...  
Keyword(s):  
Inflammatory Arthritis ◽  
Molecular Mechanisms ◽  
Near Infrared ◽  
Panax Notoginseng ◽  
Muscle Cells ◽  
Lv Function ◽  
No Production ◽  
Branch Points ◽  
Hind Limbs ◽  
And Function

Abstract Background. We previous studies reveal impaired draining function of the synovial lymphatic vessel (LV) contributes to inflammatory arthritis, but the cellular and molecular mechanisms involved are not fully understood.Objective. To investigate the involvement of lymphatic muscle cells (LMCs) in mediating impaired LV function in inflammatory arthritis.Methods. TNF transgenic (TNF-Tg) arthritic mice were used. Structure and function of the LVs that drain the hind limbs were examined by whole-mount immunofluorescence staining, electron microscope, and near-infrared lymphatic imaging. Primary LMCs were treated with TNF, and the changes in proliferation, apoptosis, and functional gene expression were assessed. Roles of the herbal drug, Panax Notoginseng Saponins (PNS), in arthritis and LVs were studied.Results. TNF-Tg mice developed ankle arthritis with age, which was associated with abnormalities of LVs: 1) dilated capillary LVs with few branch points; 2) mature LVs with reduced LMC coverage and draining function; 3) degenerative and apoptotic appearance of LMCs. TNF caused LMC apoptosis, reduced expression of muscle functional genes, and promoted the production of nitric oxide (NO) by lymphatic endothelial cells (LECs). PNS attenuated arthritis, restored LMC coverage and draining function of mature LVs, inhibited TNF-mediated NO expression, and reduced LMC apoptosis.Conclusion. The impaired draining function of LVs in TNF-Tg mice involves LMC apoptosis. TNF promotes LMC death directly and indirectly via NO production by LECs. PNS attenuates arthritis, improves LVs, and prevents TNF-induced LMC apoptosis by inhibiting NO production of LECs. LMCs contribute to the dysfunction of synovial LVs in inflammatory arthritis.

scholarly journals Lymphatic muscle cells contribute to dysfunction of the synovial lymphatic system in inflammatory arthritis in mice

2021 ◽  
Author(s):  
Qianqian Liang ◽  
Li Zhang ◽  
Hao Xu ◽  
Jinlong Li ◽  
Yan Chen ◽  
...  
Keyword(s):  
Inflammatory Arthritis ◽  
Molecular Mechanisms ◽  
Near Infrared ◽  
Panax Notoginseng ◽  
Muscle Cells ◽  
Lv Function ◽  
No Production ◽  
Branch Points ◽  
Hind Limbs ◽  
And Function

Abstract Background. Our previous studies reveal that impaired draining function of the synovial lymphatic vessel (LV) contributes to the pathogenesis of inflammatory arthritis, but the cellular and molecular mechanisms involved are not fully understood.Objective. To investigate the involvement of lymphatic muscle cells (LMCs) in mediating impaired LV function in inflammatory arthritis. Methods. TNF transgenic (TNF-Tg) arthritic mice were used. Structure and function of the LVs that drained the hind limbs were examined by whole-mount immunofluorescence staining, electron microscopy, and near-infrared lymphatic imaging. Primary LMCs were treated with TNF, and the changes in proliferation, apoptosis, and functional gene expression were assessed. The roles of the herbal drug, Panax Notoginseng Saponins (PNS), in arthritis and LVs were studied.Results. TNF-Tg mice developed ankle arthritis with age, which was associated with abnormalities of LVs: 1) dilated capillary LVs with few branch points; 2) mature LVs with reduced LMC coverage and draining function; 3) degenerative and apoptotic appearance of LMCs. TNF caused LMC apoptosis, reduced expression of muscle functional genes, and promoted the production of nitric oxide (NO) by lymphatic endothelial cells (LECs). PNS attenuated arthritis, restored LMC coverage and draining function of mature LVs, inhibited TNF-mediated NO expression, and reduced LMC apoptosis. Conclusion. The impaired draining function of LVs in TNF-Tg mice involves LMC apoptosis. TNF promotes LMC death directly and indirectly via NO production by LECs. PNS attenuates arthritis, improves LVs, and prevents TNF-induced LMC apoptosis by inhibiting NO production of LECs. LMCs contribute to the dysfunction of synovial LVs in inflammatory arthritis.

scholarly journals Hypercapnia induces injury to alveolar epithelial cells via a nitric oxide-dependent pathway

2000 ◽  
Vol 279 (5) ◽  
pp. L994-L1002 ◽  
Author(s):  
John D. Lang ◽  
Phillip Chumley ◽  
Jason P. Eiserich ◽  
Alvaro Estevez ◽  
Thad Bamberg ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Epithelial Cells ◽  
Cell Injury ◽  
Inflammatory Responses ◽  
Alveolar Epithelial Cells ◽  
No Production ◽  
Inflammatory Reactions ◽  
Alveolar Epithelial ◽  
And Function ◽  
The Impact

Ventilator strategies allowing for increases in carbon dioxide (CO2) tensions (hypercapnia) are being emphasized to ameliorate the consequences of inflammatory-mediated lung injury. Inflammatory responses lead to the generation of reactive species including superoxide (O2 −), nitric oxide (·NO), and their product peroxynitrite (ONOO−). The reaction of CO2 and ONOO− can yield the nitrosoperoxocarbonate adduct ONOOCO2 −, a more potent nitrating species than ONOO−. Based on these premises, monolayers of fetal rat alveolar epithelial cells were utilized to investigate whether hypercapnia would modify pathways of ·NO production and reactivity that impact pulmonary metabolism and function. Stimulated cells exposed to 15% CO2 (hypercapnia) revealed a significant increase in ·NO production and nitric oxide synthase (NOS) activity. Cell 3-nitrotyrosine content as measured by both HPLC and immunofluorescence staining also increased when exposed to these same conditions. Hypercapnia significantly enhanced cell injury as evidenced by impairment of monolayer barrier function and increased induction of apoptosis. These results were attenuated by the NOS inhibitor N-monomethyl-l-arginine. Our studies reveal that hypercapnia modifies ·NO-dependent pathways to amplify cell injury. These results affirm the underlying role of ·NO in tissue inflammatory reactions and reveal the impact of hypercapnia on inflammatory reactions and its potential detrimental influences.

scholarly journals Identification of Potential Calorie Restriction-Mimicking Yeast Mutants with Increased Mitochondrial Respiratory Chain and Nitric Oxide Levels

2011 ◽  
Vol 2011 ◽  
pp. 1-16 ◽  
Author(s):  
Bin Li ◽  
Craig Skinner ◽  
Pablo R. Castello ◽  
Michiko Kato ◽  
Erin Easlon ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Calorie Restriction ◽  
Mitochondrial Respiration ◽  
Molecular Mechanisms ◽  
Mitochondrial Respiratory Chain ◽  
Yeast Cells ◽  
Mitochondrial Activity ◽  
No Production ◽  
Hypoxic Conditions ◽  
Yeast Mutants

Calorie restriction (CR) induces a metabolic shift towards mitochondrial respiration; however, molecular mechanisms underlying CR remain unclear. Recent studies suggest that CR-induced mitochondrial activity is associated with nitric oxide (NO) production. To understand the role of mitochondria in CR, we identify and studySaccharomyces cerevisiaemutants with increased NO levels as potential CR mimics. Analysis of the top 17 mutants demonstrates a correlation between increased NO, mitochondrial respiration, and longevity. Interestingly, treating yeast with NO donors such as GSNO (S-nitrosoglutathione) is sufficient to partially mimic CR to extend lifespan. CR-increased NO is largely dependent on mitochondrial electron transport and cytochrome c oxidase (COX). Although COX normally produces NO under hypoxic conditions, CR-treated yeast cells are able to produce NO under normoxic conditions. Our results suggest that CR may derepress some hypoxic genes for mitochondrial proteins that function to promote the production of NO and the extension of lifespan.

scholarly journals Prolactin activation of mammary nitric oxide synthase: molecular mechanisms

2002 ◽  
Vol 28 (1) ◽  
pp. 45-51 ◽  
Author(s):  
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Intracellular Calcium ◽  
Molecular Mechanisms ◽  
Mammary Epithelial Cells ◽  
Calcium Ionophore ◽  
Mammary Epithelial ◽  
No Production ◽  
2B Protein ◽  
Oxide Synthase

Prolactin (PRL) is capable of stimulating both calcium and nitric oxide (NO) accumulation in mammary epithelial cells within 15min. A calcium ionophore was also able to stimulate NO levels to an extent similar to that generated by PRL. Furthermore, maximal concentrations of PRL and the ionophore were not additive, suggesting that they were both using the same pathway, i.e. calcium. Finally, the depletion of intracellular calcium completely abrogated the effect of PRL on NO production. No other pathway known to affect NO synthase (NOS) influenced the action of PRL. Specifically, manipulations of protein phosphatase 2B, protein kinase B (PKB), protein kinase C (PKC), and arginine transport did not alter the activation of NOS by PRL. Therefore, the ability of PRL to stimulate NO production at 15min can be completely explained by its ability to elevate intracellular calcium.

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