scholarly journals The Endothelial ADMA/NO Pathway in Hypoxia-Related Chronic Respiratory Diseases

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Nicole Lüneburg ◽  
Lars Harbaum ◽  
Jan K. Hennigs
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Beneficial Effect ◽  
Cardiovascular System ◽  
Therapeutic Target ◽  
Respiratory Diseases ◽  
Asymmetric Dimethylarginine ◽  
Dimethylarginine Dimethylaminohydrolase ◽  
Chronic Respiratory Diseases ◽  
Promising Therapeutic Target

Since its discovery, many adhere to the view that asymmetric dimethylarginine (ADMA), as an inhibitor of the synthesis of nitric oxide (NO), contributes to the pathogenesis of various diseases. Particularly, this is evident in disease of the cardiovascular system, in which endothelial dysfunction results in an imbalance between vasoconstriction and vasodilatation. Even if increased ADMA concentrations are closely related to an endothelial dysfunction, several studies pointed to a potential beneficial effect of ADMA, mainly in the context of angioproliferative disease such as cancer and fibrosis. Antiproliferative properties of ADMA independent of NO have been identified in this context. In particular, the regulation of ADMA by its degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH) is the object of many studies. DDAH is discussed as a promising therapeutic target for the indirect regulation of NO. In hypoxia-related chronic respiratory diseases, this controversy discussion of ADMA and DDAH is particularly evident and is therefore subject of this review.

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.

scholarly journals Indolent course of tubulointerstitial disease in a mouse model of subpressor, low-dose nitric oxide synthase inhibition

2008 ◽  
Vol 295 (3) ◽  
pp. F717-F725 ◽  
Author(s):  
Adelina Stoessel ◽  
Alexander Paliege ◽  
Franziska Theilig ◽  
Francesco Addabbo ◽  
Brian Ratliff ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Basement Membrane ◽  
Mouse Model ◽  
Asymmetric Dimethylarginine ◽  
In Vivo Model ◽  
No Production ◽  
Collagen Xviii

Deficiency of nitric oxide (NO) represents a consistent manifestation of endothelial dysfunction (ECD), and the accumulation of asymmetric dimethylarginine occurs early in renal disease. Here, we confirmed in vitro and in vivo the previous finding that a fragment of collagen XVIII, endostatin, was upregulated by chronic inhibition of NO production and sought to support a hypothesis that primary ECD contributes to nephrosclerosis in the absence of other profibrotic factors. To emulate more closely the indolent course of ECD, the study was expanded to an in vivo model with NG-monomethyl-l-arginine(l-NMMA; mimics effects of asymmetric dimethylarginine) administered to mice in the drinking water at subpressor doses of 0.3 and 0.8 mg/ml for 3–6 mo. This resulted in subtle but significant morphological alterations detected in kidneys of mice chronically treated with l-NMMA: 1) consistent perivascular expansion of interstitial matrix components at the inner stripe of the outer medulla and 2) collagen XVIII/endostatin abundance. Ultrastructural abnormalities were detected in l-NMMA-treated mice: 1) increased activity of the interstitial fibroblasts; 2) occasional detachment of endothelial cells from the basement membrane; 3) splitting of the vascular basement membrane; 4) focal fibrosis; and 5) accumulation of lipofuscin by interstitial fibroblasts. Preembedding labeling of microvasculature with anti-CD31 antibodies showed infiltrating leukocytes and agglomerating platelets attaching to the visibly intact or denuded capillaries. Collectively, the data indicate that the mouse model of subpressor chronic administration of l-NMMA is not a robust one (endothelial pathology visible only ultrastructurally), and yet it closely resembles the natural progression of endothelial dysfunction, microvascular abnormalities, and associated tubulointerstitial scarring.

scholarly journals The effects of renal replacement therapy on plasma, asymmetric dimethylarginine, nitric oxide and C-reactive protein levels

2008 ◽  
Vol 31 (1) ◽  
pp. 1 ◽  
Author(s):  
Halfize Uzun ◽  
Dildar Konukoglu ◽  
Mine Besler ◽  
Fusun Erdenen ◽  
Can Sezgin ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Risk Factors ◽  
Renal Replacement Therapy ◽  
Endothelial Dysfunction ◽  
Replacement Therapy ◽  
Asymmetric Dimethylarginine ◽  
C Reactive Protein ◽  
Plasma Urea ◽  
Reactive Protein ◽  
Plasma Adma

Purpose: Asymmetric dimethylarginine (ADMA), nitric oxide (NOx), and C-reactive protein (CRP) are important risk factors for endothelial dysfunction and mortality in the end stage renal diseases population. The aim of the study was to investigate the relationship between renal replacement therapy and endothelial dysfunction. Methods: Plasma NOx, ADMA and CRP levels were examined in randomized selected 30 patients with chronic kidney diseases (CKD), 28 patients receiving continuous ambulatory peritoneal dialysis (PD) and 30 patients receiving regular hemodialysis (HD) and age-matched 20 healthy controls. The duration of dialysis was from 4, 5 to 11, and 6 years, respectively. Results: CKD patients had higher plasma ADMA (1.26±0.53?mol/L) and CRP levels (1.02±025mg/L) and lower NOx levels (28.6±5.4?mol/L) than controls (0.45±0.20; 0.65± 0.45; 32.5±37 respectively, P < 0.001).Plasma NOx and CRP levels were higher in HD patients (32.9±5.5?mol/L, P < 0.05 and 4.59±3.18mg/L, P < 0.001) and plasma ADMA and CRP levels were higher in PD patients (1.82±0.98?mol/L, P < 0.001 and 2.40±1.53mg/L, P < 0.001) than in CKD patients. PD patients had higher plasma ADMA levels (P < 0.05) and lower plasma NOx and CRP levels than HD patients (P < 0.001 and P < 0.001). Plasma ADMA levels were negatively correlated with NOx levels in all patient groups (P < 0.001). Plasma CRP levels in CKD and HD patients were positively correlated with plasma urea levels (r:0,437, P < 0,001) and duration of dialysis (r:0,370, P < 0.01), respectively. Conclusion: CRP and ADMA may be emerging as important risk factors for atherosclerosis in dialysis patients. Reduced NO elaboration secondary to accumulation of ADMA and elevated inflammation may be important pathogenic factors for endothelial dysfunction in both dialysis treatment strategies.

scholarly journals The Delivery of Nitric Oxide in the Cardiovascular System: Implication for Clinical Diagnosis and Therapy

2021 ◽  
Author(s):  
Tianxiang Ma ◽  
Zhexi Zhang ◽  
Yu Chen ◽  
Haoran Su ◽  
Xiaoyan Deng ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Endothelial Dysfunction ◽  
Cardiovascular System ◽  
Diagnostic Methods ◽  
Fast Reaction ◽  
Clinical Images ◽  
Diagnosis And Therapy ◽  
Reaction Characteristics

Nitric oxide (NO) is a key molecule in cardiovascular homeostasis and its abnormal delivery is highly associated with the occurrence and development of cardiovascular disease (CVD). The assessment and manipulation of NO delivery is crucial to the diagnosis and therapy of CVD, such as endothelial dysfunction, atherosclerotic progression, pulmonary hypertension, and cardiovascular manifestations of Coronavirus (COVID-19). However, due to the low concentration and fast reaction characteristics of NO in cardiovascular system, the clinical applications centered on the NO delivery are challenging. In this tutorial review, we first summarized the methods to estimate the in vivo NO delivery process based on the clinical images and mathematical modeling to assess the endothelial function and vulnerability of atherosclerotic plaque. Then, the emerging bioimaging technologies that have the potential to directly measure the arterial NO concentration were discussed, including the Raman spectroscopy and electrochemical sensor. Aside from the diagnostic methods, therapies aimed at controlling NO delivery to regulate CVD were reviewed, including the inhaled NO therapy to treat the pulmonary hypertension and COVID-19, stem cell therapy and NO-releasing platform to treat endothelial dysfunction and atherosclerosis.

scholarly journals Delivery of Nitric Oxide in the Cardiovascular System: Implications for Clinical Diagnosis and Therapy

2021 ◽  
Vol 22 (22) ◽  
pp. 12166
Author(s):  
Tianxiang Ma ◽  
Zhexi Zhang ◽  
Yu Chen ◽  
Haoran Su ◽  
Xiaoyan Deng ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Endothelial Dysfunction ◽  
Computational Modeling ◽  
Cardiovascular System ◽  
Electrochemical Sensors ◽  
Diagnostic Methods ◽  
Diagnosis And Therapy ◽  
No Release

Nitric oxide (NO) is a key molecule in cardiovascular homeostasis and its abnormal delivery is highly associated with the occurrence and development of cardiovascular disease (CVD). The assessment and manipulation of NO delivery is crucial to the diagnosis and therapy of CVD, such as endothelial dysfunction, atherosclerotic progression, pulmonary hypertension, and cardiovascular manifestations of coronavirus (COVID-19). However, due to the low concentration and fast reaction characteristics of NO in the cardiovascular system, clinical applications centered on NO delivery are challenging. In this tutorial review, we first summarized the methods to estimate the in vivo NO delivery process, based on computational modeling and flow-mediated dilation, to assess endothelial function and vulnerability of atherosclerotic plaque. Then, emerging bioimaging technologies that have the potential to experimentally measure arterial NO concentration were discussed, including Raman spectroscopy and electrochemical sensors. In addition to diagnostic methods, therapies aimed at controlling NO delivery to regulate CVD were reviewed, including the NO release platform to treat endothelial dysfunction and atherosclerosis and inhaled NO therapy to treat pulmonary hypertension and COVID-19. Two potential methods to improve the effectiveness of existing NO therapy were also discussed, including the combination of NO release platform and computational modeling, and stem cell therapy, which currently remains at the laboratory stage but has clinical potential for the treatment of CVD.

scholarly journals MARKERS OF ENDOTHELIAL DYSFUNCTION: PATHOGENETIC ROLE AND DIAGNOSTIC SIGNIFICANCE

2019 ◽  
Vol 64 (1) ◽  
pp. 34-41 ◽  
Author(s):  
T. V. Stepanova ◽  
A. N. Ivanov ◽  
N. E. Tereshkina ◽  
E. B. Popyhova ◽  
D. D. Lagutina
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Asymmetric Dimethylarginine ◽  
Vascular Endothelial ◽  
C Reactive Protein ◽  
Pathogenetic Role ◽  
Reactive Protein ◽  
Von Willebrand ◽  
Endothelial Growth Factor ◽  
Willebrand Factor

Endothelial dysfunction (ED) is considered one of the pathogenetic mechanisms of a whole range of diseases. Detection of specific biochemical markers in the blood is an effective way to ED diagnostics that characterize the vascular endothelium state. This review highlights the pathogenetic role of the factors synthesized by endotheliocytes whose level changes in biological fluids reflect violations of the endothelium basic physiological properties: vasomotor function, thromboresistance, angiogenesis regulation, barrier and adhesion functions. In particular, the participation of nitric oxide metabolites, asymmetric dimethylarginine, endothelin-1, metabolic products of arachidonic acid, von Willebrand factor, thrombomodulin, vascular endothelial growth factor, vasohibine-1 and adhesion molecules in the onset and development of ED are reviewed. The diagnostic significances of factors damaging endothelium, such as C-reactive protein, homocysteine and 8-hydroxy-2’-deoxyguanosine, are discussed. In addition, the literature data of recent years about the prospects of clinical implication the detection of the above-mentioned factors which indicates structural and functional endothelial cells damage are given. Particular attention is paid to the ED markers detection prognostic significance and the possibility of their practical use for the ED diagnosis. The search of literature for the current review was conducted in RSIC, CyberLeninka, Scopus, Web of Science, MedLine and PubMed databases from 2012 to 2018 using the following keywords: endothelial dysfunction, nitric oxide, asymmetric dimethylarginine, endothelin-1, prostacyclin, thromboxane A2, epoxyeicosatrienoic acids, von Willebrand factor, thrombomodulin, vascular endothelial growth factor, vasohibin-1, adhesive molecules, C-reactive protein, homocysteine, and 8-hydroxy-2-deoxyguanosine.

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