scholarly journals Uncoupling of Vascular Nitric Oxide Synthase Caused by Intermittent Hypoxia

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Mohammad Badran ◽  
Bisher Abuyassin ◽  
Saeid Golbidi ◽  
Najib Ayas ◽  
Ismail Laher
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Intermittent Hypoxia ◽  
Asymmetric Dimethylarginine ◽  
Chronic Intermittent Hypoxia ◽  
No Production ◽  
Diabetic Mice ◽  
Enos Uncoupling ◽  
Obstructive Sleep ◽  
Oxide Synthase

Objective. Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is often present in diabetic (DB) patients. Both conditions are associated with endothelial dysfunction and cardiovascular disease. We hypothesized that diabetic endothelial dysfunction is further compromised by CIH.Methods. Adult male diabetic (BKS.Cg-Dock7m+/+Leprdb/J) (db/db) mice (10 weeks old) and their heterozygote littermates were subjected to CIH or intermittent air (IA) for 8 weeks. Mice were separated into 4 groups: IA (intermittent air nondiabetic), IH (intermittent hypoxia nondiabetic), IADB (intermittent air diabetic), and IHDB (intermittent hypoxia diabetic) groups. Endothelium-dependent and endothelium-independent relaxation and modulation by basal nitric oxide (NO) were analyzed using wire myograph. Plasma 8-isoprostane, interleukin-6 (IL-6), and asymmetric dimethylarginine (ADMA) were measured using ELISA. Uncoupling of eNOS was measured using dihydroethidium (DHE) staining.Results. Endothelium-dependent vasodilation and basal NO production were significantly impaired in the IH and IADB group compared to IA group but was more pronounced in IHDB group. Levels of 8-isoprostane, IL-6, ADMA, and eNOS uncoupling were ≈2-fold higher in IH and IADB groups and were further increased in the IHDB group.Conclusion. Endothelial dysfunction is more pronounced in diabetic mice subjected to CIH compared to diabetic or CIH mice alone. Oxidative stress, ADMA, and eNOS uncoupling were exacerbated by CIH in diabetic mice.

scholarly journals Alpha Lipoic Acid Improves Endothelial Function and Oxidative Stress in Mice Exposed to Chronic Intermittent Hypoxia

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Mohammad Badran ◽  
Bisher Abuyassin ◽  
Saeid Golbidi ◽  
Najib Ayas ◽  
Ismail Laher
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Intermittent Hypoxia ◽  
Chronic Intermittent Hypoxia ◽  
Alpha Lipoic Acid ◽  
Systemic Oxidative Stress ◽  
Enos Uncoupling ◽  
And Oxidative Stress

Objective. Obstructive sleep apnea (OSA) is characterized by recurrent airway collapse that causes chronic intermittent hypoxia (CIH). OSA is associated with systemic inflammation and oxidative stress resulting in endothelial dysfunction and cardiovascular disease (CVD). Alpha lipoic acid (ALA) is a potent antioxidant with anti-inflammatory properties. We hypothesized that dietary ALA can improve endothelial function of mice exposed to CIH. Methods. Mice were exposed to either CIH or intermittent air (IA) and treated with dietary ALA (0.2% w/w) or a regular chow diet for 8 weeks. Endothelial function, endothelial nitric oxide (eNOS) uncoupling, systemic oxidative stress, systemic inflammation, aortic expression of inflammatory cytokines, and antioxidant enzymes were measured after 8 weeks. Results. Mice exposed to CIH exhibited endothelial dysfunction accompanied by systemic oxidative stress and inflammation as well as increased aortic expression of inflammatory cytokines. Furthermore, CIH led to eNOS uncoupling. Treatment with dietary ALA reversed endothelial dysfunction in mice exposed to CIH, lowered systemic oxidative stress and inflammation, prevented the increases of inflammatory cytokine gene expression, increased the expression of antioxidant enzymes, and preserved eNOS in a coupled state. Conclusion. ALA attenuates endothelial dysfunction by preventing oxidative stress and inflammation and restoring nitric oxide bioavailability in mice exposed to CIH. Our data suggests the potential beneficial use of ALA as adjunctive therapy in OSA.

scholarly journals Tempol Alleviates Chronic Intermittent Hypoxia-Induced Pancreatic Injury Through Repressing Inflammation and Apoptosis

2019 ◽  
pp. 445-455
Author(s):  
Y. WANG ◽  
L. AI ◽  
B. HAI ◽  
Y. CAO ◽  
R. LI ◽  
...  
Keyword(s):  
Intermittent Hypoxia ◽  
Pancreatic Injury ◽  
Protective Role ◽  
Pancreatic Tissue ◽  
Mitogen Activated Protein Kinase ◽  
Chronic Intermittent Hypoxia ◽  
Obstructive Sleep ◽  
Mitogen Activated Protein ◽  
Induced Apoptosis ◽  
Oxide Synthase

Obstructive sleep apnea (OSA) has been demonstrated to be implicated in disorder of insulin secretion and diabetes mellitus. In this study, we aimed to evaluate the protective role of tempol, a powerful antioxidant, in chronic intermittent hypoxia (IH)-induced pancreatic injury. The rat model of OSA was established by IH exposure. The pathological changes, increased blood-glucose level, and raised proinsulin/insulin ratio in pancreatic tissues of rats received IH were effectively relieved by tempol delivery. In addition, the enhanced levels of pro-inflammatory cytokines, TNF-α, IL-1β, IL-6, and inflammatory mediators, PGE2, cyclooxygenase-2 (COX-2), NO, and inducible nitric oxide synthase (iNOS) in pancreatic tissue were suppressed by tempol. Moreover, tempol inhibited IH-induced apoptosis in pancreatic tissue as evidenced by upregulated Bcl-2 level, and downregulated Bax and cleaved caspase-3 levels. Finally, the abnormal activation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways induced by IH was restrained by tempol administration. In summary, our study demonstrates that tempol relieves IH-induced pancreatic injury by inhibiting inflammatory response and apoptosis, which provides theoretical basis for tempol as an effective treatment for OSA-induced pancreatic injury.

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.

scholarly journals Asymmetric Dimethylarginine (ADMA) and Symmetric Dimethylarginine (SDMA) Concentrations in Patients with Obesity and the Risk of Obstructive Sleep Apnea (OSA)

2019 ◽  
Vol 8 (6) ◽  
pp. 897 ◽  
Author(s):  
Yana Arlouskaya ◽  
Ada Sawicka ◽  
Marek Głowala ◽  
Joanna Giebułtowicz ◽  
Natalia Korytowska ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Asymmetric Dimethylarginine ◽  
Apnea Hypopnea Index ◽  
Enos Gene ◽  
No Production ◽  
Serum Concentrations ◽  
Symmetric Dimethylarginine ◽  
Obstructive Sleep

Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are endogenous inhibitors of nitric oxide (NO) synthesis, and play a critical role in the process of endothelial dysfunction, and are considered markers of oxidative stress. The aim of the present study was to explore relationships between ADMA and/or SDMA and the occurrence of OSA in obese patients as well as the effect of the endothelial nitric oxide synthase (eNOS) gene polymorphism, which may modify the influence of ADMA or SDMA on NO production. A total of 518 unrelated obese subjects were included in this study. Body weight, height and blood pressure were measured and data on self-reported smoking status were collected. Obstructive sleep apnea (OSA) was assessed by the apnea hypopnea index (AHI). Blood samples were collected to measure serum concentrations of glucose, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, creatinine, HbA1c (%), folic acid, vitamin B12, C-reactive protein (CRP), aspartate aminotransferase (ASP), alanine aminotransferase (ALT) and IL-6 by routine methods. The NOS3 gene G894T and 4a/4b polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. ADMA, SDMA and arginine concentrations were assessed simultaneously using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method. Adjusted multivariate logistic regression analysis showed a significant association between the occurrence of OSA and high serum ADMA levels, BMI above 40, age > 43 years, hypertension and male sex. Heterozygotes for the G894T eNOS polymorphism have the lowest serum concentrations of ADMA and SDMA, while no effect of the 4a/4b variants was observed. The results indicate that OSA in obese individuals can coexist with high ADMA levels, which appear as a potential OSA predictor.

scholarly journals Mulberry Extract Attenuates Endothelial Dysfunction through the Regulation of Uncoupling Endothelial Nitric Oxide Synthase in High Fat Diet Rats

Nutrients ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 978 ◽  
Author(s):  
Geum-Hwa Lee ◽  
The-Hiep Hoang ◽  
Eun-Soo Jung ◽  
Su-Jin Jung ◽  
Soo-Wan Chae ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Nitric Oxide Synthase ◽  
High Fat Diet ◽  
Endothelial Nitric Oxide Synthase ◽  
High Fat ◽  
Enos Uncoupling ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Dyslipidemia is associated with endothelial dysfunction, which is linked to nitric oxide (NO) biology. The coupling of endothelial NO synthase with cofactors is a major step for NO release. This study is aimed to investigate the vascular pharmacology effects of mulberry in rat thoracic aorta and human vascular endothelial cells. In vitro, we investigated the protective effects of the mulberry extract and its main component cyanidin-3-rutinoside (C-3-R), against oxidized low-density lipoprotein (ox-LDL)-induced endothelial nitric oxide synthase (eNOS) uncoupling. Whereas ox-LDL significantly decreased NO levels in endothelial cells, mulberry extract, and C-3-R significantly recovered NO levels and phospho-eNOS Thr495 and Ser1177 expression. In vivo, mulberry was administered to 60% of high-fat diet (w/w)-fed Sprague Dawley (SD) rats for six weeks, in which endothelium-dependent relaxations were significantly improved in organ bath studies and isometric tension recordings. Consistently, aortic expressions of phospho-eNOS and nitrotyrosine were increased. Mulberry also raised serum NO levels, increased phosphorylation of eNOS, and reduced nitrotyrosine and intracellular reactive oxygen species (ROS) in aortas, showing that mulberry preserves endothelium-dependent relaxation in aortas from high-fat diet rats. We suggest that this effect is mediated through enhanced NO bioavailability, in which the regulation of ROS and its reduced eNOS uncoupling are involved.

Nitric oxide and asymmetric dimethylarginine (ADMA) in malignancy associated thrombosis and their modulation by anticoagulants

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10573-10573
Author(s):  
J. Fareed ◽  
D. A. Hoppensteadt ◽  
M. Demir ◽  
O. Iqbal ◽  
W. Jeske ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Cancer Patients ◽  
Asymmetric Dimethylarginine ◽  
Oral Anticoagulants ◽  
Treated Group ◽  
Competitive Inhibitor ◽  
No Production ◽  
Open Label ◽  
Stage Renal Disease

10573 Background: Cancer associated thrombotic complications are primarily due to endothelial dysfunction and upregulation of inflammatory processes. Nitric oxide (NO) represents one of the major endothelial derived vasoactive mediators. Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of NO synthase which inhibits NO production at pathophysiologic levels. Plasma ADMA levels are upregulated in atherosclerosis, hypertension, end stage renal disease, chronic heart failure and microangiopathy. Methods: To test the hypothesis that endothelial dysfunction in cancer patients may result in increased ADMA levels, plasma samples were retrospectively analyzed from an open label, multidose, active comparator designed study in which all patients (n = 110) were initially treated with low molecular weight heparin, enoxaparin (E) at 1–1.5 mg/kg sc for 5 days and further subdivided into group E which continued to receive E and warfarin (W) group which was given oral anticoagulants for a period of up to 12 weeks. Baseline blood samples (BL), 5 days post E (IPE) and 4–6 week samples from the E and W were analyzed for ADMA and NO levels by ELISA methods. Results: Both the ADMA and NO levels were markedly elevated in cancer patients. The E treated group showed a marked decrease in the ADMA levels which persisted throughout the treatment period. However, in the W converted group the ADMA levels rebounded to an increased level indicating that E differentially regulated ADMA in these patients. The down regulation pattern of NO was similar for both E and W. Conclusions: These results suggest that patients with cancer and thrombosis exhibit simultaneous upregulation of ADMA and NO. While E and W show a differential regulation of ADMA both result in downregulation of NO. The fact that E regulates ADMA is highly suggestive of its role in iNOS regulation which may be involved in the inflammatory response in cancer patients. [Table: see text] No significant financial relationships to disclose.

Nitric oxide and asymmetric dimethylarginine and CD 40 ligand levels in malignancy associated thrombosis and their modulation by anticoagulants

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 17049-17049
Author(s):  
D. Hoppensteadt ◽  
D. Fareed ◽  
O. Iqbal ◽  
A. Lale ◽  
J. Fareed
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Cancer Patients ◽  
Asymmetric Dimethylarginine ◽  
Oral Anticoagulants ◽  
Treated Group ◽  
Competitive Inhibitor ◽  
No Production ◽  
Open Label ◽  
Vasoactive Mediators

17049 Background: Cancer associated thrombotic complications are primarily due to endothelial dysfunction and upregulation of inflammatory processes. Nitric oxide (NO) represents one of the major endothelial derived vasoactive mediators. Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of NO synthase which inhibits NO production at pathophysiologic levels. CD 40 ligand (CD 40L) is also upregulated in cancer. Methods: To test the hypothesis that endothelial dysfunction in cancer patients may result in increased ADMA levels, plasma samples were retrospectively analyzed from an open label, multidose, active comparator designed study in which all patients (n=110) were initially treated with low molecular weight heparin, enoxaparin (E) at 1–1.5 mg/kg sc for 5 days and further subdivided into group E which continued to receive E and warfarin (W) group which was given oral anticoagulants for a period of up to 12 weeks. Baseline blood samples (BL), 5 days post E (IPE) and 4–6 week samples from the E and W were analyzed for ADMA and CD 40L levels by ELISA methods. NO levels were measured using a chromogenic method. Results: The baseline levels of NO, ADMA and CD 40L levels were markedly elevated in cancer patients. The E treated group showed a marked decrease in the ADMA and CD 40L levels which persisted throughout the treatment period. However, in the W converted group the ADMA and CD 40L levels rebounded to an increased level indicating that E differentially regulated ADMA in these patients. The down regulation pattern of NO was similar for both E and W. Conclusions: These results suggest that patients with cancer and thrombosis exhibit simultaneous upregulation of ADMA, CD 40L and NO. While E and W show a differential regulation of ADMA and CD 40L, both result in a downregulation of NO. The fact that E regulates ADMA is highly suggestive of its role in iNOS regulation which may be involved in the inflammatory response in cancer patients. [Table: see text] No significant financial relationships to disclose.

Microparticles from Patients with the Acute Coronary Syndrome Impair Vasodilatation by Inhibiting the Akt/eNOS-Hsp90 Signaling Pathway

Cardiology ◽  
2015 ◽  
Vol 132 (4) ◽  
pp. 252-260 ◽  
Author(s):  
Wen-Qi Han ◽  
Feng-Jun Chang ◽  
Qun-Rang Wang ◽  
Jun-Qiang Pan
Keyword(s):  
Nitric Oxide ◽  
Acute Coronary Syndrome ◽  
Endothelial Dysfunction ◽  
Heat Shock Protein 90 ◽  
No Production ◽  
Healthy Controls ◽  
Coronary Syndrome ◽  
Enos Phosphorylation ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Objectives: Endothelial dysfunction is involved in the development of the acute coronary syndrome (ACS). Plasma microparticles (MPs) from other diseases have been demonstrated to initiate coagulation and endothelial dysfunction. However, whether MPs from ACS patients impair vasodilatation and endothelial function remains unclear. Methods: Patients (n = 62) with ACS and healthy controls (n = 30) were recruited for MP isolation. Rat thoracic aortas were incubated with MPs from ACS patients or healthy controls to determine the effects of MPs on endothelial-dependent vasodilatation, the phosphorylation of Akt and endothelial nitric oxide synthase (eNOS), the interaction of eNOS with heat shock protein 90 (Hsp90), and nitric oxide (NO) and superoxide anion (O2-) production. The origin of MPs was assessed by flow cytometry. Results: MP concentrations were increased in patients with ACS compared with healthy controls. They were positively correlated with the degree of coronary artery stenosis. MPs from ACS patients impair endothelial-dependent vasodilatation, decrease both Akt and eNOS phosphorylation, decrease the interaction between eNOS and Hsp90, and decrease NO production but increase O2- generation in rat thoracic aortas. Endothelial-derived MPs and platelet-derived MPs made up nearly 75% of MPs. Conclusions: Our data indicate that MPs from ACS patients negatively affect endothelial-dependent vasodilatation via Akt/eNOS-Hsp90 pathways.

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