scholarly journals Overexpression of Alanine-glyoxylate aminotransferase 2 Protects from Asymmetric Dimethylarginine-induced Endothelial Dysfunction and Aortic Remodeling

2021 ◽  
Author(s):  
Roman N. Rodionov ◽  
Natalia Jarzebska ◽  
Dmitrii Burdin ◽  
Vladimir Todorov ◽  
Jens Martens-Lobenhoffer ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Plasma Levels ◽  
Asymmetric Dimethylarginine ◽  
Plasma Concentrations ◽  
Cardiovascular Effects ◽  
Vascular Damage ◽  
Plasma Adma ◽  
Increased Risk ◽  
Glyoxylate Aminotransferase ◽  
Aortic Remodeling

Abstract Objective: Elevated plasma concentrations of asymmetric dimethylarginine (ADMA) are associated with an increased risk of mortality and adverse cardiovascular outcomes. ADMA can be metabolized by dimethylarginine dimethylaminohydrolases (DDAHs) and by alanine-glyoxylate aminotransferase 2 (AGXT2). Deletion of DDAH1 in mice leads to elevation of ADMA in plasma and blood pressure, while overexpression of human DDAH1 is associated with a lower plasma ADMA concentration and protective cardiovascular effects. The possible role of alternative metabolism of ADMA by AGXT2 remains to be elucidated. The goal of the current study was to test the hypothesis that transgenic overexpression of AGXT2 leads to lowering of plasma levels of ADMA and protection from vascular damage in the setting of DDAH1 deficiency.Approach and Results: We generated transgenic mice (TG) with ubiquitous overexpression of AGXT2. qPCR and Western Blot confirmed the expression of the transgene. Systemic ADMA levels were decreased by 15% in TG mice. In comparison with wild type animals plasma levels of asymmetric dimethylguanidino valeric acid (ADGV), the AGXT2 associated metabolite of ADMA, were six times higher. We crossed AGXT2 TG mice with DDAH1 knockout mice and observed that upregulation of AGXT2 lowers plasma ADMA and pulse pressure and protects the mice from endothelial dysfunction and adverse aortic remodeling.Conclusions: Upregulation of AGXT2 led to lowering of ADMA levels and protection from ADMA-induced vascular damage in the setting of DDAH1 deficiency. This is especially important, because all the efforts to develop pharmacological ADMA-lowering interventions by means of upregulation of DDAHs have been unsuccessful.

Abstract 453: Transgenic Overexpression of Alanine-glyoxylate Aminotransferase 2 in Mice Lowers Asymmetric Dimethylarginine and Improves Vasomotor Function

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Natalia Jarzebska ◽  
Roman N Rodionov ◽  
Dmitri Burdin ◽  
Silke Brilloff ◽  
Vladimir T Todorov ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Asymmetric Dimethylarginine ◽  
Vasomotor Function ◽  
Arterial Blood ◽  
Plasma Adma ◽  
Increased Risk ◽  
Glyoxylate Aminotransferase ◽  
Oxide Synthase

Background: Elevation of the endogenous inhibitor of nitric oxide synthase asymmetric dimethylarginine (ADMA) has been shown to be associated with increased risk of cardiovascular diseases. There are two major pathways of ADMA catabolism: hydrolysis to citrulline by dimethylarginine dimethylaminohydrolases (DDAH) and transamination by alanine-glyoxylate aminotransferase 2 (AGXT2) with formation of asymmetric dimethylguanidino valeric acid (ADGV). The second pathway is poorly characterized. The goal of the current study was to test the hypothesis that transgenic overexpression of AGXT2 leads to lowering of systemic levels of ADMA and improvement of vasomotor function. Methods and Results: We generated transgenic mice (TG) with ubiquitous overexpression of AGXT2 under control of the chicken beta actin (CAG) promoter. qPCR and Western Blot were used to confirm the ubiquitous expression of the transgene. There were no developmental or phenotypic changes in the TG animals. Biochemical data were generated using HPLC-MS/MS. ADMA plasma levels were decreased by 15% (p<0.05) in the TG mice, whereas ADGV plasma levels were 6 times higher in comparison with wild-types littermates (p<0.001). Lung and heart of TG animals exhibited 2 times lower tissue ADMA content in comparison with controls (p<0.05). TG mice demonstrated improved endothelium-dependent vasodilation (in response to acetylcholine) in aortic rings. The endothelium-independent relaxation (in response to sodium nitroprusside) was unchanged. There was no difference in mean arterial blood pressure measured by telemetry between the wild type and AGXT2 TG mice. In further experiments, we crossed the AGXT2 TG mice with DDAH1 KO mice and showed that upregulation of AGXT2 protects DDAH1 KO mice from elevation of plasma ADMA levels. Conclusion: In the current study we demonstrated that upregulation of AGXT2 leads to lowering of ADMA levels and improvement of endothelium-dependent relaxation in vivo. AGXT2 thereby may be a potential drug target for long-term reduction of systemic ADMA levels in cardiovascular pathologies. This is especially important, because all the efforts to develop pharmacological ADMA-lowering interventions by means of upregulation of DDAH have not been successful so far.

Effect of acute variations of insulin and glucose on plasma concentrations of asymmetric dimethylarginine in young people with Type 1 diabetes

2008 ◽  
Vol 115 (12) ◽  
pp. 361-369 ◽  
Author(s):  
M. Loredana Marcovecchio ◽  
Barry Widmer ◽  
David B. Dunger ◽  
R. Neil Dalton
Keyword(s):  
Type 1 Diabetes ◽  
Risk Factor ◽  
Young People ◽  
Asymmetric Dimethylarginine ◽  
Plasma Concentrations ◽  
Young Patients ◽  
Glucose Levels ◽  
Significant Fall ◽  
Plasma Adma

ADMA (asymmetric dimethylarginine), an endogenous inhibitor of nitric oxide synthase, is considered a major risk factor for cardiovascular disease and progression of renal disease. In the present study we aim to investigate the effect of acute variations in plasma glucose and insulin on plasma ADMA levels in young people with T1D (Type 1 diabetes). Fifteen young patients (ten males) with T1D, median age 18.3 (13.2–24.4) years, HbA1c (glycated haemoglobin) 9% (6.4–13.6%), underwent an overnight (18:00–08:00 hours) variable insulin infusion for euglycaemia, followed by a hyperinsulinaemic–euglycaemic clamp (08:00–12:00 hours). Blood samples were collected every 15 min for determination of ADMA, SDMA (symmetric dimethylarginine), valine, phenylalanine, arginine, creatinine and glucose. Insulin levels were assessed every 30 min. During the overnight period, glucose levels increased following the evening meal. In response to the protein intake there was a significant increase in ADMA, arginine, valine, phenylalanine and creatinine. For the remaining part of the night, glucose levels progressively decreased reaching 5 mmol/l by 04:00 hours. ADMA and SDMA did not change significantly. During the hyperinsulinaemic clamp, a significant fall in ADMA was observed, from 0.468±0.056 to 0.364±0.050 μmol/l (P<0.001). A significant fall was also found in SDMA, valine, phenylalanine, arginine and the ADMA/SDMA ratio (all P<0.001), but not in creatinine levels. No correlation was found between insulin sensitivity and ADMA. We conclude that acute changes in glycaemia do not significantly affect plasma ADMA levels whereas infusion of insulin significantly reduces ADMA, suggesting an important role for insulin in the regulation of this cardiovascular risk factor.

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.

Elevated levels of asymmetric dimethylarginine (ADMA) as a marker of cardiovascular disease and mortality

2005 ◽  
Vol 43 (10) ◽  
Author(s):  
Rainer H. Böger ◽  
Renke Maas ◽  
Friedrich Schulze ◽  
Edzard Schwedhelm
Keyword(s):  
Cardiovascular Disease ◽  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Asymmetric Dimethylarginine ◽  
Metabolic Diseases ◽  
Serum Levels ◽  
Major Adverse Cardiovascular Events ◽  
Blood Levels ◽  
Increased Risk ◽  
Vasoactive Mediator

AbstractThe endothelium plays a crucial role in the maintenance of vascular tone and structure by releasing the endothelium-derived vasoactive mediator, nitric oxide (NO). NO is formed in healthy vascular endothelium from the amino acid precursor L-arginine. Endothelial dysfunction is caused by various cardiovascular risk factors, metabolic diseases, and systemic or local inflammation. One mechanism that explains the occurrence of endothelial dysfunction is the presence of elevated blood levels of asymmetric dimethylarginine (ADMA) – an L-arginine analogue that inhibits NO formation and thereby can impair vascular function. Accumulating evidence from prospective clinical studies suggests that elevated plasma or serum levels of ADMA are associated with an increased risk of major adverse cardiovascular events. This article gives an updated overview of the currently available literature on ADMA and cardiovascular disease from prospective clinical trials. Recently, advances have been made in the development of analytical methods that are reliable and fast enough to allow determination of ADMA in clinical routine.

Part II: Biochemical changes after pituitary adenylate cyclase-activating polypeptide-38 infusion in migraine patients

Cephalalgia ◽  
2016 ◽  
Vol 37 (2) ◽  
pp. 136-147 ◽  
Author(s):  
Song Guo ◽  
Anne Luise Haulund Vollesen ◽  
Young Bae Lee Hansen ◽  
Erik Frandsen ◽  
Malene Rohr Andersen ◽  
...  
Keyword(s):  
Adenylate Cyclase ◽  
Plasma Levels ◽  
Intravenous Infusion ◽  
Plasma Concentrations ◽  
Pituitary Hormones ◽  
Control Group ◽  
Gene Variant ◽  
Biochemical Variables ◽  
Increased Risk ◽  
Pituitary Adenylate Cyclase

Background Intravenous infusion of pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) provokes migraine attacks in 65–70% of migraine without aura (MO) patients. We investigated whether PACAP38 infusion causes changes in the endogenous production of PACAP38, vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP), tumour necrosis factor alpha (TNFα), S100 calcium binding protein B (S100B), neuron-specific enolase and pituitary hormones in migraine patients. Methods We allocated 32 previously genotyped MO patients to receive intravenous infusion PACAP38 (10 pmol/kg/minute) for 20 minutes and recorded migraine-like attacks. Sixteen of the patients were carriers of the risk allele rs2274316 ( MEF2D), which confers increased risk of MO and may regulate PACAP38 expression, and 16 were non-carriers. We collected blood samples at baseline and 20, 30, 40, 60 and 90 minutes after the start of the infusion. A control group of six healthy volunteers received intravenous saline. Results PACAP38 infusion caused significant changes in plasma concentrations of VIP ( p = 0.026), prolactin ( p = 0.011), S100B ( p < 0.001) and thyroid-stimulating hormone (TSH; p = 0.015), but not CGRP ( p = 0.642) and TNFα ( p = 0.535). We found no difference in measured biochemical variables after PACAP38 infusion in patients who later developed migraine-like attacks compared to those who did not ( p > 0.05). There was no difference in the changes of biochemical variables between patients with and without the MEF2D-associated gene variant ( p > 0.05). Conclusion PACAP38 infusion elevated the plasma levels of VIP, prolactin, S100B and TSH, but not CGRP and TNFα. Development of delayed migraine-like attacks or the presence of the MEF2D gene variant was not associated with pre-ictal changes in plasma levels of neuropeptides, TNFα and pituitary hormones.

Reduced renal plasma clearance does not explain increased plasma asymmetric dimethylarginine in hypertensive subjects with mild to moderate renal insufficiency

2012 ◽  
Vol 303 (1) ◽  
pp. F149-F156 ◽  
Author(s):  
Rianne A. Ronden ◽  
Alfons J. H. M. Houben ◽  
Tom Teerlink ◽  
Jaap A. Bakker ◽  
Jörgen Bierau ◽  
...  
Keyword(s):  
Renal Insufficiency ◽  
Confidence Intervals ◽  
Plasma Clearance ◽  
Asymmetric Dimethylarginine ◽  
Plasma Concentrations ◽  
Minor Importance ◽  
Nitric Oxide Synthase Inhibitor ◽  
Hypertensive Patients ◽  
Plasma Adma ◽  
Moderate Renal Insufficiency

Plasma concentrations of the nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) increase already in the early stages of renal insufficiency. There is no agreement as to whether reduced renal plasma clearance (RPCL) contributes to this increase. Therefore, we investigated the relationship between estimated glomerular filtration rate (eGFR), RPCL, and plasma ADMA and SDMA in essential hypertensive patients with mild to moderate renal insufficiency. In 171 patients who underwent renal angiography, we drew blood samples from the aorta and both renal veins and measured mean renal blood flow (MRBF) using the 133Xe washout technique. RPCL was calculated using arteriovenous concentration differences and MRBF. After correction for potential confounders, reduced eGFR was associated with higher plasma ADMA and SDMA [standardized regression coefficient (β) = −0.22 (95% confidence intervals: −0.41, −0.04) and β = −0.66 (95% confidence intervals: −0.83, −0.49), respectively]. However, eGFR was not independently associated with RPCL of ADMA. Moreover, reduced RPCL of ADMA was not associated with higher plasma ADMA. Contrary to ADMA, reduced eGFR was indeed associated with lower RPCL of SDMA [β = 0.21 (95% confidence intervals: 0.02, 0.40)] . In conclusion, our findings indicate that RPCL of ADMA is independent of renal function in hypertensive patients with mild to moderate renal insufficiency. Unlike the case for SDMA, reduced RPCL of ADMA is of minor importance for the increase in plasma ADMA in these patients, which indicates that increased plasma ADMA in this population is not a direct consequence of the kidneys failing as a plasma ADMA-regulating organ.

Endothelial dysfunction and raised plasma concentrations of asymmetric dimethylarginine in pregnant women who subsequently develop pre-eclampsia

The Lancet ◽  
2003 ◽  
Vol 361 (9368) ◽  
pp. 1511-1517 ◽  
Author(s):  
Makrina D Savvidou ◽  
Aroon D Hingorani ◽  
Dimitrios Tsikas ◽  
Jürgen C Frölich ◽  
Patrick Vallance ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Pregnant Women ◽  
Asymmetric Dimethylarginine ◽  
Plasma Concentrations

scholarly journals Cigarette smoking cessation increases plasma levels of several antioxidant micronutrients and improves resistance towards oxidative challenge

2003 ◽  
Vol 90 (1) ◽  
pp. 147-150 ◽  
Author(s):  
M. Cristina Polidori ◽  
Patrizia Mecocci ◽  
Wilhelm Stahl ◽  
Helmut Sies
Keyword(s):  
Oxidative Stress ◽  
Smoking Cessation ◽  
Cardiovascular Diseases ◽  
Cigarette Smoking ◽  
Plasma Levels ◽  
Plasma Concentrations ◽  
Preventive Strategy ◽  
Plasma Resistance ◽  
Increased Risk ◽  
Oxidative Challenge

Cigarette smoking is associated epidemiologically with increased risk of cardiovascular diseases, but the pathophysiological mechanisms are still not fully understood. There is evidence that smoking is related to increased free radical production and antioxidant depletion, but the effects of smoking cessation on plasma concentrations of antioxidants and susceptibility to oxidative stress are largely unknown. Plasma levels of vitamins A, C, E, uric acid, total thiols, carotenoids (including lutein, zeaxanthin, β-cryptoxanthin, lycopene, α- and β-carotene) and malondialdehyde (MDA, a biomarker of lipid peroxidation) were measured in fifteen healthy, normolipidaemic subjects (seven males, eight females, 35·2 (sd2·3) years) before and 4 weeks after smoking cessation. To determine plasma resistance towards oxidative challenge, plasma was incubated for up to 5h with the peroxyl radical-generator 2,2′-azobis(2-amidinopropane) (AAPH); MDA and ascorbate levels were measured at various time points. The concentrations of all plasma antioxidants were lower before smoking cessation than afterwards; MDA levels were higher before than after termination of smoking. Upon AAPH exposure, the consumption of plasma ascorbate and the production of MDA occurred at a significantly faster rate before smoking cessation as compared with afterwards. Cigarette smoking cessation is followed by a marked increase in plasma antioxidant concentrations and substantially improves plasma resistance towards oxidative challenge. Given the importance of cigarette smoking as a risk factor for cardiovascular diseases and the pathophysiological role played by oxidative stress in these illnesses, quitting smoking represents an irreplaceable preventive strategy against tobacco-induced oxidative stress and vascular damage.

Plasma Concentrations of Asymmetric Dimethylarginine, an Endogenous Nitric Oxide Synthetase Inhibitor, Are Elevated in Sickle Cell Patients but Do Not Increase during Painful Crises.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3795-3795
Author(s):  
Pearl Landburg ◽  
Tom Teerlink ◽  
Sigrid de Jong ◽  
Frits A. Muskiet ◽  
Ashley J. Duits ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Sickle Cell ◽  
Asymmetric Dimethylarginine ◽  
Plasma Concentrations ◽  
Endothelial Activation ◽  
Healthy Controls ◽  
Asymptomatic Patients ◽  
Plasma Adma ◽  
One Way Anova ◽  
Painful Crisis

Abstract Plasma concentrations of asymmetric dimethylarginine (ADMA), an endogenously produced inhibitor of nitric oxide (NO) synthase, are elevated and related to endothelial activation in clinically asymptomatic patients with sickle cell disease (SCD). However, ADMA concentrations have not been defined during acute vaso-occlusive complications. We determined plasma ADMA and arginine concentrations in 96 samples (40 collected in the clinically asymptomatic state and 56 collected at presentation with a painful crisis) of 44 HbSS patients (mean age 32±13 years, m:f=23:21) and in 39 samples (22 collected in the clinically asymptomatic state and 17 collected at presentation with a painful crisis) of 22 HbSC patients (mean age 30±14 years, m:f=10:12). Thirty-five race, sex and age matched HbAA blood donors served as healthy controls. Plasma ADMA concentrations were elevated in asymptomatic sickle cell patients as compared to healthy controls (HbSS: mean 0.7±0.1 umol/L, HbSC mean 0.5±0.1 umol/L, HbAA mean 0.4±0.1 umol/L; p<0.001 one way ANOVA). Plasma arginine concentrations were lower in asymptomatic HbSS patients as compared to asymptomatic HbSC patients and healthy controls (HbSS: mean 59.6±25.8 umol/L, HbSC mean 75.5±25.8 umol/L, HbAA mean 74.0±27.1 umol/L; p=0.03 one way ANOVA). Ratio’s of ADMA to arginine (ADMA/Arginine × 1000) were highest in HbSS patients (HbSS: mean 16.2±11.6, HbSC mean 7.8±2.9, HbAA mean 6.3±3.2; p=0.001 one way ANOVA). In both HbSS and HbSC patients, neither ADMA (p=0.17/p=0.57), arginine (p=0.13/p=0.18) nor the ADMA/arginine ratio (p=0.88/p=0.08) differed between the asymptomatic phase and at presentation with a painful crisis. In conclusion, even though ADMA is elevated in SCD and therefore may well be involved in the development of chronic organ complications by limiting NO availability, ADMA concentrations are not affected during acute painful sickle cell crises.

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