scholarly journals Decreased Expression and Uncoupling of Endothelial Nitric Oxide Synthase in the Cerebral Cortex of Rats with Thioacetamide-Induced Acute Liver Failure

2021 ◽  
Vol 22 (13) ◽  
pp. 6662
Author(s):  
Krzysztof Milewski ◽  
Anna Maria Czarnecka ◽  
Jan Albrecht ◽  
Magdalena Zielińska
Keyword(s):  
Nitric Oxide ◽  
Liver Failure ◽  
Acute Liver Failure ◽  
Molecular Abnormalities ◽  
Enos Uncoupling ◽  
Ros Accumulation ◽  
No Signaling ◽  
Nos Inhibitor ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Acute liver failure (ALF) is associated with deregulated nitric oxide (NO) signaling in the brain, which is one of the key molecular abnormalities leading to the neuropsychiatric disorder called hepatic encephalopathy (HE). This study focuses on the effect of ALF on the relatively unexplored endothelial NOS isoform (eNOS). The cerebral prefrontal cortices of rats with thioacetamide (TAA)-induced ALF showed decreased eNOS expression, which resulted in an overall reduction of NOS activity. ALF also decreased the content of the NOS cofactor, tetrahydro-L-biopterin (BH4), and evoked eNOS uncoupling (reduction of the eNOS dimer/monomer ratio). The addition of the NO precursor L-arginine in the absence of BH4 potentiated ROS accumulation, whereas nonspecific NOS inhibitor L-NAME or EDTA attenuated ROS increase. The ALF-induced decrease of eNOS content and its uncoupling concurred with, and was likely causally related to, both increased brain content of reactive oxidative species (ROS) and decreased cerebral cortical blood flow (CBF) in the same model.

Increasing dihydrobiopterin causes dysfunction of endothelial nitric oxide synthase in rats in vivo

2011 ◽  
Vol 301 (3) ◽  
pp. H721-H729 ◽  
Author(s):  
Katsuhiko Noguchi ◽  
Naobumi Hamadate ◽  
Toshihiro Matsuzaki ◽  
Mayuko Sakanashi ◽  
Junko Nakasone ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Endothelial Nitric Oxide Synthase ◽  
Control Treatment ◽  
Enos Uncoupling ◽  
Nos Inhibitor ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
First Time

An elevation of oxidized forms of tetrahydrobiopterin (BH4), especially dihydrobiopterin (BH2), has been reported in the setting of oxidative stress, such as arteriosclerotic/atherosclerotic disorders, where endothelial nitric oxide synthase (eNOS) is dysfunctional, but the role of BH2 in the regulation of eNOS activity in vivo remains to be evaluated. This study was designed to clarify whether increasing BH2 concentration causes endothelial dysfunction in rats. To increase vascular BH2 levels, the BH2 precursor sepiapterin (SEP) was intravenously given after the administration of the specific dihydrofolate reductase inhibitor methotrexate (MTX) to block intracellular conversion of BH2 to BH4. MTX/SEP treatment did not significantly affect aortic BH4 levels compared with control treatment. However, MTX/SEP treatment markedly augmented aortic BH2 levels (291.1 ± 29.2 vs. 33.4 ± 6.4 pmol/g, P < 0.01) in association with moderate hypertension. Treatment with MTX alone did not significantly alter blood pressure or BH4 levels but decreased the BH4-to-BH2 ratio. Treatment with MTX/SEP, but not with MTX alone, impaired ACh-induced vasodilator and depressor responses compared with the control treatment (both P < 0.05) and also aggravated ACh-induced endothelium-dependent relaxations ( P < 0.05) of isolated aortas without affecting sodium nitroprusside-induced endothelium-independent relaxations. Importantly, MTX/SEP treatment significantly enhanced aortic superoxide production, which was diminished by NOS inhibitor treatment, and the impaired ACh-induced relaxations were reversed with SOD ( P < 0.05), suggesting the involvement of eNOS uncoupling. These results indicate, for the first time, that increasing BH2 causes eNOS dysfunction in vivo even in the absence of BH4 deficiency, demonstrating a novel insight into the regulation of endothelial function.

Hypothermia-induced cardioprotection using extended ischemia and early reperfusion cooling

2007 ◽  
Vol 292 (4) ◽  
pp. H1995-H2003 ◽  
Author(s):  
Zuo-Hui Shao ◽  
Wei-Tien Chang ◽  
Kim Chai Chan ◽  
Kim R. Wojcik ◽  
Chin-Wang Hsu ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Therapeutic Hypothermia ◽  
Optimal Timing ◽  
No Production ◽  
Early Reperfusion ◽  
No Signaling ◽  
Nos Inhibitor ◽  
Oxide Synthase ◽  
Pkc Activation

Optimal timing of therapeutic hypothermia for cardiac ischemia is unknown. Our prior work suggests that ischemia with rapid reperfusion (I/R) in cardiomyocytes can be more damaging than prolonged ischemia alone. Also, these cardiomyocytes demonstrate protein kinase C (PKC) activation and nitric oxide (NO) signaling that confer protection against I/R injury. Thus we hypothesized that hypothermia will protect most using extended ischemia and early reperfusion cooling and is mediated via PKC and NO synthase (NOS). Chick cardiomyocytes were exposed to an established model of 1-h ischemia/3-h reperfusion, and the same field of initially contracting cells was monitored for viability and NO generation. Normothermic I/R resulted in 49.7 ± 3.4% cell death. Hypothermia induction to 25°C was most protective (14.3 ± 0.6% death, P < 0.001 vs. I/R control) when instituted during extended ischemia and early reperfusion, compared with induction after reperfusion (22.4 ± 2.9% death). Protection was completely lost if onset of cooling was delayed by 15 min of reperfusion (45.0 ± 8.2% death). Extended ischemia/early reperfusion cooling was associated with increased and sustained NO generation at reperfusion and decreased caspase-3 activation. The NOS inhibitor Nω-nitro-l-arginine methyl ester (200 μM) reversed these changes and abrogated hypothermia protection. In addition, the PKCε inhibitor myr-PKCε v1-2 (5 μM) also reversed NO production and hypothermia protection. In conclusion, therapeutic hypothermia initiated during extended ischemia/early reperfusion optimally protects cardiomyocytes from I/R injury. Such protection appears to be mediated by increased NO generation via activation of protein kinase Cε; nitric oxide synthase.

Tackling endothelial dysfunction by modulating NOS uncoupling: new insights into its pathogenesis and therapeutic possibilities

2012 ◽  
Vol 302 (5) ◽  
pp. E481-E495 ◽  
Author(s):  
Rinrada Kietadisorn ◽  
Rio P. Juni ◽  
An L. Moens
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Therapeutic Interventions ◽  
Enos Uncoupling ◽  
Underlying Causes ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Endothelial nitric oxide synthase (eNOS) serves as a critical enzyme in maintaining vascular pressure by producing nitric oxide (NO); hence, it has a crucial role in the regulation of endothelial function. The bioavailability of eNOS-derived NO is crucial for this function and might be affected at multiple levels. Uncoupling of eNOS, with subsequently less NO and more superoxide generation, is one of the major underlying causes of endothelial dysfunction found in atherosclerosis, diabetes, hypertension, cigarette smoking, hyperhomocysteinemia, and ischemia/reperfusion injury. Therefore, modulating eNOS uncoupling by stabilizing eNOS activity, enhancing its substrate, cofactors, and transcription, and reversing uncoupled eNOS are attractive therapeutic approaches to improve endothelial function. This review provides an extensive overview of the important role of eNOS uncoupling in the pathogenesis of endothelial dysfunction and the potential therapeutic interventions to modulate eNOS for tackling endothelial dysfunction.

Abstract 15999: The Divergent Effects of Exercise Training After Myocardial Infarction or Pressure Overload Depend Critically on Endothelial Nitric Oxide Synthase

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Yanti Octavia ◽  
Elza v Deel ◽  
Monique d Waard ◽  
Martine d Boer ◽  
An Moens ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Exercise Training ◽  
Endothelial Nitric Oxide Synthase ◽  
Pressure Overload ◽  
Beneficial Effects ◽  
Enhanced Chemiluminescence ◽  
Enos Uncoupling ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

AIMS: Beneficial effects of aerobic exercise training are widely recognized. However, previously we discovered that the positive effects of exercise depend on the underlying cause of cardiac failure. Here we tested the hypothesis that endothelial nitric oxide synthase (eNOS) dependent regulation of the balance between nitric oxide and superoxide (O2•-) is critically involved in determining the effects of exercise. METHODS: Mice were exposed to 8 weeks of voluntary wheel running exercise training (EX) or sedentary housing (SED) immediately following myocardial infarction (MI), pressure overload from a transverse aortic constriction (TAC), or sham (SH) surgery. Subsequently, left ventricular (LV) ejection fraction (EF) was measured by echocardiography and Picrosirius Red staining was performed to measure collagen content. Additionally, total and NOS-dependent LV O2•- were measured using lucigenin-enhanced chemiluminescence without or with NOS inhibitor, L-NAME. eNOS uncoupling was evaluated by determining eNOS monomer dimer protein ratio and peroxynitrite (ONOO-) levels were measured through luminol-enhanced chemiluminescence. RESULTS: Cardiac dysfunction and fibrosis were ameliorated by exercise in MI but not in TAC mice (Table 1). MI and TAC both increased LV O2•- levels. Strikingly, EX diminished O2•- generation in MI, but exacerbated O2•- generation in TAC (Table 1). Furthermore, the EX-induced increase in O2•- levels in TAC were largely NOS-dependent. Accordingly, MI and TAC-induced eNOS uncoupling was normalized by EX in MI but aggravated in TAC mice (Table 1). Similarly, increased ONOO- levels following MI and TAC were diminished by EX in MI, but exacerbated by EX in TAC (Table 1). CONCLUSIONS: EX reduces eNOS-mediated cardiac oxidative stress in MI. In contrast, beneficial effects of EX are lacking in cardiac pressure-overload following TAC, due to EX-induced aggravation of ONOO- formation, eNOS uncoupling and concomitant oxidative stress.

Abstract 111: Xanthine Oxidoreductase Plays a Key Role in Nitrate, Nitrite and Nitric Oxide Homeostasis When the Endothelial Nitric Oxide Synthase is Compromised

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Maria Peleli ◽  
Christa Zollbrecht ◽  
Marcelo Montenegro ◽  
Michael Hezel ◽  
Eddie Weitzberg ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Primary Source ◽  
No Production ◽  
Xanthine Oxidoreductase ◽  
Physiological Conditions ◽  
Inorganic Nitrate ◽  
Nos Inhibitor ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Xanthine oxidoreductase (XOR) is generally known as a source of superoxide production, but this enzyme has also been suggested to mediate NO production via reduction of inorganic nitrate (NO 3 - ) and nitrite(NO 2 - ). This pathway for NO generation is of particular importance during certain pathologies, whereas endothelial NO synthase (eNOS) is the primary source of vascular NO generation under normal physiological conditions. The exact interplay between the NOS and XOR-derived NO is not yet fully elucidated. The aim of the present study was to investigate if eNOS deficiency is partly compensated by XOR upregulation and sensitization of the NO 3 - - NO 2 - - NO pathway. NO 3 - and NO 2 - were similar between naïve eNOS KO and wildtype (wt) mice, but reduced upon chronic treatment with the non-selective NOS inhibitor L-NAME (wt: 25.0±5.2, eNOS KO: 39.2±6.4, L-NAME: 8.2±1.6 μ NO 3 - -, wt: 0.38±0.07, eNOS KO: 0.42±0.04, L-NAME: 0.12±0.02 μ NO 2 - ). XOR function was upregulated in eNOS KO compared with wt mice [(mRNA: wt 1±0.07, eNOS KO 1.38±0.17), (activity: wt 825±54, eNOS KO 1327±280 CLU/mg/min), (uric acid: wt 32.87±1.53, eNOS KO 43.23±3.54 μ)]. None of these markers of XOR activity was increased in nNOS KO and iNOS KO mice. Following acute dose of NO 3 - (10 mg/kg bw, i.p.), the increase of plasma NO 2 - was more pronounced in eNOS KO (+0.51±0.13 μ) compared with wt (+0.22±0.09 μ), and this augmented response in the eNOS KO was abolished by treatment with the highly selective XOR inhibitor febuxostat (FEB). Liver from eNOS KO had higher reducing capacity of NO 2 - to NO compared with wt, and this effect was attenuated by FEB (Δppb of NO: wt +8.7±4.2, eNOS KO +44.2±15.0, wt+FEB +22.2±9.6, eNOS KO+FEB +26.8±10.2). Treatment with FEB increased blood pressure in eNOS KO (ΔMAP:+10.2±5.6 mmHg), but had no effect in wt (ΔMAP:-0.6±3.3 mmHg). Supplementation with NO 3 - (10 mM, drinking water) reduced blood pressure in eNOS KO (ΔMAP: -6.3±2.2 mmHg), and this effect was abolished by FEB (ΔMAP: +1.1±1.9 mmHg). In conclusion, upregulated and altered XOR function in conditions with eNOS deficiency can facilitate the NO 3 - - NO 2 - - NO pathway and hence play a significant role in vascular NO homeostasis.

scholarly journals eNOS activation and NO function: Structural motifs responsible for the posttranslational control of endothelial nitric oxide synthase activity

2011 ◽  
Vol 210 (3) ◽  
pp. 271-284 ◽  
Author(s):  
Ruslan Rafikov ◽  
Fabio V Fonseca ◽  
Sanjiv Kumar ◽  
Daniel Pardo ◽  
Charles Darragh ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Posttranslational Modifications ◽  
Endothelial Nitric Oxide Synthase ◽  
Regulatory Region ◽  
Enos Uncoupling ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
Nitric Oxide Synthase Activity

Rather than being a constitutive enzyme as was first suggested, endothelial nitric oxide synthase (eNOS) is dynamically regulated at the transcriptional, posttranscriptional, and posttranslational levels. This review will focus on how changes in eNOS function are conferred by various posttranslational modifications. The latest knowledge regarding eNOS targeting to the plasma membrane will be discussed as the role of protein phosphorylation as a modulator of catalytic activity. Furthermore, new data are presented that provide novel insights into how disruption of the eNOS dimer prevents eNOS uncoupling and the production of superoxide under conditions of elevated oxidative stress and identifies a novel regulatory region we have termed the ‘flexible arm’.

scholarly journals Can endothelial hemoglobin-α regulate nitric oxide vasodilatory signaling?

2017 ◽  
Vol 312 (4) ◽  
pp. H854-H866 ◽  
Author(s):  
Jaimit Parikh ◽  
Adam Kapela ◽  
Nikolaos M. Tsoukias
Keyword(s):  
Mathematical Modeling ◽  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Endothelial Nitric Oxide Synthase ◽  
Cellular Models ◽  
No Signaling ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

We used mathematical modeling to investigate nitric oxide (NO)-dependent vasodilatory signaling in the arteriolar wall. Detailed continuum cellular models of calcium (Ca2+) dynamics and membrane electrophysiology in smooth muscle and endothelial cells (EC) were coupled with models of NO signaling and biotransport in an arteriole. We used this theoretical approach to examine the role of endothelial hemoglobin-α (Hbα) as a modulator of NO-mediated myoendothelial feedback, as previously suggested in Straub et al. ( Nature 491: 473–477, 2012). The model considers enriched expression of inositol 1,4,5-triphosphate receptors (IP3Rs), endothelial nitric oxide synthase (eNOS) enzyme, Ca2+-activated potassium (KCa) channels and Hbα in myoendothelial projections (MPs) between the two cell layers. The model suggests that NO-mediated myoendothelial feedback is plausible if a significant percentage of eNOS is localized within or near the myoendothelial projection. Model results show that the ability of Hbα to regulate the myoendothelial feedback is conditional to its colocalization with eNOS near MPs at concentrations in the high nanomolar range (>0.2 μM or 24,000 molecules). Simulations also show that the effect of Hbα observed in in vitro experimental studies may overestimate its contribution in vivo, in the presence of blood perfusion. Thus, additional experimentation is required to quantify the presence and spatial distribution of Hbα in the EC, as well as to test that the strong effect of Hbα on NO signaling seen in vitro, translates also into a physiologically relevant response in vivo. NEW & NOTEWORTHY Mathematical modeling shows that although regulation of nitric oxide signaling by hemoglobin-α (Hbα) is plausible, it is conditional to its presence in significant concentrations colocalized with endothelial nitric oxide synthase in myoendothelial projections. Additional experimentation is required to test that the strong effect of Hbα seen in vitro translates into a physiologically relevant response in vivo

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