scholarly journals The role of tetrahydrobiopterin in inflammation and cardiovascular disease

2012 ◽  
Vol 108 (11) ◽  
pp. 832-839 ◽  
Author(s):  
Eileen McNeill ◽  
Keith Channon
Keyword(s):  
Nitric Oxide ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Cell Types ◽  
No Production ◽  
Major Site ◽  
Cellular Redox ◽  
Oxide Synthase ◽  
New Evidence

SummaryThe cofactor tetrahydrobiopterin (BH4) is required for nitric oxide (NO) production by all nitric oxide synthase (NOS) enzymes and is a key regulator of cellular redox signalling. When BH4 levels become limiting NOS enzymes become ‘uncoupled’ and produce superoxide rather than NO. Endothelial cell BH4 is required for the maintenance of vascular function through NO production, and reduced BH4 levels are associated with vascular dysfunction. Evidence increasingly points to important roles for BH4 and NOS enzymes in other vascular cell types. Leukocytes have a fundamental role in atherosclerosis, and new evidence points to a role in the control of hypertension. Leukocytes are a major site of iNOS expression, and the regulation of this isoform is another mechanism by which BH4 availability may modulate disease. This review provides an overview of BH4 control of NOS function in both endothelial cells and leukocytes in the context of vascular disease and current therapeutic evaluations.

The role of nitric oxide synthase/nitric oxide in vascular smooth muscle control

Perfusion ◽  
2000 ◽  
Vol 15 (2) ◽  
pp. 97-104 ◽  
Author(s):  
D Bradford Sanders ◽  
Tara Kelley ◽  
Douglas Larson
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Nitric Oxide Synthase ◽  
Vascular Smooth Muscle ◽  
Vascular Function ◽  
No Production ◽  
Amyl Nitrite ◽  
Vascular Compliance ◽  
Oxide Synthase

Vascular compliance is dependent on endogenous and exogenous sources of nitric oxide (NO). In a discussion of therapeutics and NO derived via nitric oxide synthase (NOS) enzymes, it is necessary to examine the pathways of each drug to provide the clinical perfusionist with a greater understanding of the role of NOS/NO in vascular function. Endothelial-derived NO is a contributor in the vasoregulation of vascular smooth muscle. Therapeutics seek to mimic the vasodilatory effects of the endogenous NO. The therapeutics included in this review are nitroglycerin, nitroprusside, amyl nitrite, and inhalation of NO. L-Arginine supplementation provides additional substrate for the endogenous pathway that can augment NO production. NO is a small bioactive molecule involved in various biochemical pathways. Dysregulation of NO production can impair normal physiologic control of vascular compliance. Therefore, the purpose of this review is to provide the perfusionist with an understanding of the biochemical and pharmacological aspects of NOS/NO associated with vascular function.

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.

Effects of homocysteine on endothelial nitric oxide production

2000 ◽  
Vol 279 (4) ◽  
pp. F671-F678 ◽  
Author(s):  
Xiaohui Zhang ◽  
Hong Li ◽  
Haoli Jin ◽  
Zachary Ebin ◽  
Sergey Brodsky ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Redox State ◽  
Calcium Ionophore ◽  
No Production ◽  
Cellular Redox ◽  
A Cell ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
Peroxynitrite Scavengers

Hyperhomocysteinemia (HHCy) is an independent and graded cardiovascular risk factor. HHCy is prevalent in patients with chronic renal failure, contributing to the increased mortality rate. Controversy exists as to the effects of HHCy on nitric oxide (NO) production: it has been shown that HHCy both increases and suppresses it. We addressed this problem by using amperometric electrochemical NO detection with a porphyrinic microelectrode to study responses of endothelial cells incubated with homocysteine (Hcy) to the stimulation with bradykinin, calcium ionophore, or l-arginine. Twenty-four-hour preincubation with Hcy (10, 20, and 50 μM) resulted in a gradual decline in responsiveness of endothelial cells to the above stimuli. Hcy did not affect the expression of endothelial nitric oxide synthase (eNOS), but it stimulated formation of superoxide anions, as judged by fluorescence of dichlorofluorescein, and peroxynitrite, as detected by using immunoprecipitation and immunoblotting of proteins modified by tyrosine nitration. Hcy did not directly affect the ability of recombinant eNOS to generate NO, but oxidation of sulfhydryl groups in eNOS reduced its NO-generating activity. Addition of 5-methyltetrahydrofolate restored NO responses to all agonists tested but affected neither the expression of the enzyme nor formation of nitrotyrosine-modified proteins. In addition, a scavenger of peroxynitrite or a cell-permeant superoxide dismutase mimetic reversed the Hcy-induced suppression of NO production by endothelial cells. In conclusion, electrochemical detection of NO release from cultured endothelial cells demonstrated that concentrations of Hcy >20 μM produce a significant indirect suppression of eNOS activity without any discernible effects on its expression. Folates, superoxide ions, and peroxynitrite scavengers restore the NO-generating activity to eNOS, collectively suggesting that cellular redox state plays an important role in HCy-suppressed NO-generating function of this enzyme.

Parasite killing in murine malaria does not require nitric oxide production

Parasitology ◽  
1999 ◽  
Vol 118 (2) ◽  
pp. 139-143 ◽  
Author(s):  
N. FAVRE ◽  
B. RYFFEL ◽  
W. RUDIN
Keyword(s):  
Nitric Oxide ◽  
Blood Stage ◽  
No Production ◽  
Nos Inhibitor ◽  
Oxide Synthase ◽  
Deficient Mice ◽  
Stage Parasite ◽  
Blood Stage Malaria ◽  
Inducible Nitric Oxide

Nitric oxide (NO) production has been suggested to play a role as effector molecule in the control of the malarial infections. However, the roles of this molecule are debated. To assess whether blood-stage parasite killing is NO dependent, we investigated the course of blood-stage Plasmodium chabaudi chabaudi (Pcc) infections in inducible nitric oxide synthase (iNOS)-deficient mice. Parasitaemia, haematological alterations, and survival were not affected by the lack of iNOS. To exclude a role of NO produced by other NOS, controls included NO suppression by oral administration of aminoguanidine (AG), a NOS inhibitor. As in iNOS-deficient mice, no difference in the parasitaemia course, survival and haematological values was observed after AG treatment. Our results indicate that NO production is not required for protection against malaria in our murine experimental model. However, C57BL/6 mice treated with AG lost their resistance to Pcc infections, suggesting that the requirement for NO production for parasite killing in murine blood-stage malaria might be strain dependent.

scholarly journals Regulatory Role of GSK-3βon NF-κB, Nitric Oxide, and TNF-αin Group A Streptococcal Infection

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Yu-Tzu Chang ◽  
Chia-Ling Chen ◽  
Chiou-Feng Lin ◽  
Shiou-Ling Lu ◽  
Miao-Huei Cheng ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Mouse Model ◽  
Group A Streptococcus ◽  
Glycogen Synthase ◽  
Critical Issue ◽  
No Production ◽  
Group A ◽  
Oxide Synthase

Group A streptococcus (GAS) imposes a great burden on humans. Efforts to minimize the associated morbidity and mortality represent a critical issue. Glycogen synthase kinase-3β(GSK-3β) is known to regulate inflammatory response in infectious diseases. However, the regulation of GSK-3βin GAS infection is still unknown. The present study investigates the interaction between GSK-3β, NF-κB, and possible related inflammatory mediators in vitro and in a mouse model. The results revealed that GAS could activate NF-κB, followed by an increased expression of inducible nitric oxide synthase (iNOS) and NO production in a murine macrophage cell line. Activation of GSK-3βoccurred after GAS infection, and inhibition of GSK-3βreduced iNOS expression and NO production. Furthermore, GSK-3βinhibitors reduced NF-κB activation and subsequent TNF-αproduction, which indicates that GSK-3βacts upstream of NF-κB in GAS-infected macrophages. Similar to the in vitro findings, administration of GSK-3βinhibitor in an air pouch GAS infection mouse model significantly reduced the level of serum TNF-αand improved the survival rate. The inhibition of GSK-3βto moderate the inflammatory effect might be an alternative therapeutic strategy against GAS infection.

Role of inducible nitric oxide synthase in the regulation of leucocyte recruitment

2000 ◽  
Vol 100 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Michael J. HICKEY
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Nitric Oxide Synthase ◽  
Cell Types ◽  
Adhesive Interactions ◽  
Oxide Synthase ◽  
Leucocyte Recruitment

Constitutively produced nitric oxide released by endothelial cells has been shown to act as an endogenous agent which inhibits the rolling and adhesion of leucocytes in the microcirculation. However, during various types of inflammation, expression of the inducible form of nitric oxide synthase (iNOS) can dramatically increase the amount of nitric oxide present in tissues. Furthermore, as iNOS can be expressed by a wide variety of cell types, the distribution of nitric oxide is likely to be altered relative to that in unstimulated tissue. Under these conditions, it is less well understood whether iNOS-derived nitric oxide retains the anti-adhesive capabilities of constitutively produced nitric oxide. This review summarizes work done to examine this issue. Three main approaches have been used. In vitro studies have examined the role of iNOS in adhesive interactions between stimulated endothelial cells and leucocytes, providing evidence of an anti-adhesive effect of iNOS. In addition, the role of iNOS has been examined in vivo in animal models of inflammation using pharmacological iNOS inhibitors. These experiments were extended by the advent of the iNOS-deficient (iNOS-/-) mouse. Intravital microscopy studies of these mice have indicated that, under conditions of low-dose endotoxaemia, iNOS-derived nitric oxide can inhibit leucocyte rolling and adhesion. The potential mechanisms for these effects are discussed. In contrast, several other studies have observed either no effect or an enhancing effect of iNOS on inflammatory leucocyte recruitment. Taken together, these studies suggest that the importance of iNOS in modulating leucocyte recruitment can vary according to the type of inflammatory response.

scholarly journals Control of IntracellularFrancisella tularensisby Different Cell Types and the Role of Nitric Oxide

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Sarah L. Newstead ◽  
Amanda J. Gates ◽  
M. Gillian Hartley ◽  
Caroline A. Rowland ◽  
E. Diane Williamson ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cell Line ◽  
Rational Design ◽  
Cell Types ◽  
No Production ◽  
Macrophage Cell Line ◽  
Macrophage Cell ◽  
Schu S4 ◽  
Intracellular Infections

Reactive nitrogen is critical for the clearance ofFrancisella tularensisinfections. Here we assess the role of nitric oxide in control of intracellular infections in two murine macrophage cell lines of different provenance: the alveolar macrophage cell line, MH-S, and the widely used peritoneal macrophage cell line, J774A.1. Cells were infected with the highly virulent Schu S4 strain or with the avirulent live vaccine strain (LVS) with and without stimuli. Compared to MH-S cells, J774A.1 cells were unresponsive to stimulation and were able to control the intracellular replication of LVS bacteria, but not of Schu S4. In MH-S cells, Schu S4 demonstrated control over cellular NO production. Despite this, MH-S cells stimulated with LPS or LPS and IFN-γwere able to control intracellular Schu S4 numbers. However, only stimulation with LPS induced significant cellular NO production. Combined stimulation with LPS and IFN-γproduced a significant reduction in intracellular bacteria that occurred whether high levels of NO were produced or not, indicating that NO secretion is not the only defensive cellular mechanism operating in virulentFrancisellainfections. Understanding howF. tularensisinteracts with host macrophages will help in the rational design of new and effective therapies.

scholarly journals Investigation of Role of Nitric Oxide in Protection from Bordetella pertussis Respiratory Challenge

2002 ◽  
Vol 70 (2) ◽  
pp. 679-684 ◽  
Author(s):  
C. Canthaboo ◽  
D. Xing ◽  
X. Q. Wei ◽  
M. J. Corbel
Keyword(s):  
Nitric Oxide ◽  
Bordetella Pertussis ◽  
Knockout Mice ◽  
No Production ◽  
Wild Type ◽  
Respiratory Challenge ◽  
Inos Knockout Mice ◽  
Oxide Synthase

ABSTRACT The mechanism whereby whole-cell pertussis vaccines (WCV) confer protection against Bordetella pertussis is still not fully understood. We have previously reported that macrophage activation produced by vaccination with WCV is associated with induction of NO synthesis by macrophages in response to in vitro stimulation with B. pertussis antigens. To determine whether NO production is an effector of protection or simply a marker of activation, the susceptibility of inducible nitric oxide synthase (type II, iNOS) knockout mice to infection with B. pertussis was examined. We showed that iNOS knockout mice were more susceptible to B. pertussis respiratory challenge than wild-type mice. iNOS-deficient mice also developed a less effective protective response than wild-type mice after the same immunization with WCV. This suggests that NO plays an important role in effecting protection against B. pertussis challenge.

scholarly journals The fundamental role of increased production of nitric oxide in lipopolysaccharide-induced embryonic resorption in mice

Reproduction ◽  
2003 ◽  
pp. 95-110 ◽  
Author(s):  
DG Ogando ◽  
D Paz ◽  
M Cella ◽  
AM Franchi
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
No Production ◽  
Uterine Arteries ◽  
Decidual Cells ◽  
Embryonic Resorption ◽  
High Concentrations ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Nitric oxide (NO) fulfils important functions during pregnancy and has a role in implantation, decidualization, vasodilatation and myometrial relaxation. However, at high concentrations, such as those that are produced in sepsis, NO has toxic effects as it is a free radical. The aim of this study was to characterize uterine and decidual NO production in lipopolysaccharide (LPS)-induced embryonic resorption in mice and to determine which isoforms of nitric oxide synthase (NOS) take part. LPS produced 100% embryonic resorption at 24 h, with complete fetus expulsions at 48 h. Decidual and uterine NO production were increased by LPS, with maximum production at 6 h. This increase was due to the induction of expression of inducible nitric oxide synthase (iNOS) isoform in the decidua and uterus, and neuronal nitric oxide synthase (nNOS) isoform in the decidua, as detected by western blot analysis and immunohistochemistry. LPS increased iNOS expression in decidual and myometrial cells and increased nNOS expression in decidual cells. In addition, LPS caused fibrinolysis and infiltration of mesometrial decidua by macrophages positive for iNOS and CD14 (LPS receptor). Endothelial nitric oxide synthase (eNOS) was found in decidual and uterine arteries but LPS did not modify its expression. LPS induced CD14 expression in endometrial glands, and this could have amplified the inflammatory response. Aminoguanidine, an inhibitor of iNOS activity, totally reversed the LPS-induced embryonic resorption. This result could be explained by an inhibition of the increase in NO production but also by an inhibition of the cellular infiltration and fibrinolysis. These results show that NO fulfils a fundamental role in LPS-induced embryonic resorption.

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