Reduction In Asymmetric Dimethylarginine Levels Research Articles

Asymmetric dimethylarginine correlates with indicators of prethrombotic state in patients with nonvalvular atrial fibrillation.

The mechanism of asymmetric dimethylarginine (ADMA) in thrombosis in patients with nonvalvular atrial fibrillation (NVAF) is still unclear. Our aim was to investigate the relationship between ADMA and indicators of prethrombotic state in NVAF patients and to analyze the predictive role of ADMA in NVAF thrombosis. A total of 192 NVAF patients were continuously selected from January 2023 to October 2023. Plasma ADMA levels were measured by high-performance liquid chromatography. P-selectin (P-sel), von Willebrand factor (vWF), D-dimer (D-D), and plasminogen activator inhibitor-1 (PAI-1) levels were measured by enzyme-linked immunosorbent assay (ELISA). Nitric oxide (NO) levels were measured by the nitrate reductase assay for plasma nitrite/nitrate, then the Griess method (Shanghai Hailian Biotechnology Co., Shanghai, China) was used to calculate plasma NO levels. In our study, ADMA levels were significantly elevated and positively correlated with P-sel, vWF, D-D, and PAI-1, whereas NO levels were significantly negatively correlated with these prethrombotic factors in NVAF. Furthermore, multifactorial logistic regression analysis showed that ADMA and LA diameter were independent predictors of high thrombosis risk (CHA2DS2-VASc ≥2 score) in patients with NVAF. Our findings suggested that ADMA correlated with the prethrombotic state in NVAF and that reduction of ADMA levels in NVAF patients may be a novel therapeutic strategy for thrombosis risk reduction.

MO1008IMPACT OF RAMIPRIL ON ENDOTHELIAL DYSFUNCTION IN CHILDREN ON REGULAR HEMODIALYSIS

Abstract Background and Aims Endothelial dysfunction is an important risk factor for cardiovascular disease and therefore for increased mortality in end-stage renal disease patients. Asymmetric dimethyl arginine (ADMA), a potent inhibitor of nitric oxide synthase, strongly contributes to endothelial dysfunction. In dialysis patients, ADMA levels are markedly elevated. Previous studies have shown that angiotensin-converting enzyme inhibitors (ACEIs) can significantly reduce ADMA levels in a variety of patients. In contrast, a previous study suggested that short-term treatment with ACEIs may even increase ADMA levels in adult patients on maintenance hemodialysis. However, no study has evaluated the effect of ACEIs in pediatric patients undergoing hemodialysis. Method We conducted a prospective, randomized, double-blinded and placebo-controlled trial (NCT04582097) at two nephrology centers in Cairo, Egypt. Patients below the age of 16 years and on regular hemodialysis for 6 months or longer were eligible for inclusion. Exclusion criteria at screening included uncontrolled hypertension, serum potassium level > 5.5 mmol/L, acute infection or treatment with immunosuppressive agents within the previous month, known intolerance of ACEI treatment and inability to discontinue previous ACEI or angiotensin receptor blocker treatment. A total of 135 eligible patients (mean age, 12.6 years; range 7-15 years; 53.3% males) were randomly (1:1) assigned to once oral daily treatment with identical capsules containing either 2.5 mg ramipril (n=68) or placebo (n=67) for four months. Systolic and diastolic blood pressure (BP) and serum ADMA concentrations were measured as primary efficacy and serum potassium levels as primary safety parameter. Results At baseline, systolic and diastolic BP and ADMA levels were similar between both treatment groups (Table). After four months, both systolic and diastolic BP were significantly lower in the ramipril compared to the placebo group. Treatment with ramipril resulted in a profound reduction in ADMA levels (-77% compared to baseline) while ADMA levels were unchanged in the placebo group after four months (p <0.001). Serum levels of potassium increase in both groups with no reported symptoms of severe hyperkalemia No serious adverse events were reported in neither group. Conclusion Ramipril treatment in pediatric patients on maintenance hemodialysis causes a marked reduction in ADMA levels. This may contribute to improved endothelial vascular function besides its efficacious BP lowering effect.

The ameliorative effect of angiotensin 1-7 on experimentally induced-preeclampsia in rats: Targeting the role of peroxisome proliferator-activated receptors gamma expression & asymmetric dimethylarginine

This study was designed to explore the effect of angiotensin 1-7 (Ang 1–7) on experimentally induced-preeclampsia in Wistar rats targeting the role of peroxisome proliferator-activated receptors gamma expression (PPARs-γ) & asymmetric dimethylarginine (ADMA). 30 female Wistar rats were divided into three groups: Normal pregnant (NP), preeclampsia (PE), and preeclampsia treated with Ang 1–7 (PE + Ang 1–7) groups. Reduced uterine perfusion pressure (RUPP) model was induced on GD14. On GD18, protein in urine, urine volume and urinary sodium excretion were determined. On GD19, the systolic blood pressure (SBP) was measured, and the gene expression of PPARs-γ were determined. The serum samples were separated for determination of Ang 1–7, ADMA, soluble fms-like tyrosine kinase (sFlt-1), vascular endothelial growth factor (VEGF), nitric oxide (NO) products, endothelial nitric oxide synthase (eNOS) activity, interleukin-6 (IL-6), interleukin-10 (IL-10), malondialdehyde (MDA), and total anti-oxidant capacity (T-AOC). Compared to NP group, SBP, urine protein, serum levels of ADMA, sFlt-1, IL-6 and MDA significantly increased, while expression of PPARs-γ, serum levels of Ang 1–7, VEGF, NO products, eNOS, IL-10 and T-AOC significantly decreased in PE group, while treatment of Ang 1–7 significantly ameliorated all these studied parameters as compared to PE group. We concluded that Ang 1–7 attenuated the symptoms of preeclampsia, which might be via increasing the expression of PPARs-γ and reduction of ADMA levels which could explain its anti-hypertensive, anti-angiogenic, anti-inflammatory and antioxidant effects.

Early regression of coronary artery remodeling with esmolol and DDAH/ADMA pathway in hypertensive rats.

Our preclinical study demonstrated that esmolol produces early regression of left ventricular hypertrophy in arterial hypertension. The aim of this study was to assess the effects of short-term esmolol therapy on the regression of left anterior descending artery remodeling in spontaneously hypertensive rats (SHRs), and to determine whether the asymmetric dimethylarginine (ADMA)/dimethylarginine dimethylaminohydrolase (DDAH) pathway, a regulator of nitric oxide (NO) bioavailability, accounted for this regression. Fourteen-month-old male SHRs were treated intravenously with vehicle (SHR, n=15) or esmolol (SHR-E, n=20) (300 μg kg-1 min-1). Age-matched, vehicle-treated male Wistar-Kyoto rats (WKY, n=15) served as controls. SHRs were also treated with nitroglycerin (SHR-N, n=5). After 48 h, the left anterior descending artery structure and morphology were assessed, and dose-response curves for 5-hydroxytryptamine (5-HT, 10-9-3 × 10-5 mol l-1) were constructed. ADMA concentrations in plasma and left ventricle and DDAH activity in tissue were analyzed. Wall thickness and cross-sectional area were significantly lower after treatment with esmolol in SHR-E than in SHR. Media thickness and smooth muscle cell count were lower in SHR-E than in SHR. Esmolol induced a significant reduction in adventitial cell count in SHR-E. The area under the concentration-response curves was significantly higher in SHR than in SHR-E, as were the esmolol normalized coronary artery contracting responses to 5-HT. We found significantly lower ADMA levels and significantly higher DDAH activity in the ventricle in SHR-E than in SHR. The protective effect of esmolol on the regression of left anterior descending artery remodeling may be related to the reduction in ADMA levels.

Comparision of Effects of Rosuvastatin Versus Atorvastatin Treatment on Plasma Levels of Asymmetric Dimethylarginine in Patients With Hyperlipidemia Having Coronary Artery Disease

Elevated plasma levels of asymmetric dimethylarginine (ADMA) are prevalent in patients with hypercholesterolemia and coronary artery disease. A total of 83 patients with hypercholesterolemia and angiographically documented mild coronary artery stenosis were randomized to rosuvastatin treatment (20 mg) or atorvastatin treatment (40 mg) once daily for 6 weeks after a 4-week dietary lead-in phase. Both statins decreased total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglyceride levels effectively. Only rosuvastatin increased high-density lipoprotein cholesterol (HDL-C) levels. Both rosuvastatin and atorvastatin decreased plasma ADMA levels; rosuvastatin had a significantly greater effect. The reduction in ADMA levels were correlated with the reduction in TC and LDL-C levels as well as LDL-C-HDL-C ratio. Treatment with rosuvastatin or atorvastatin in patients with hyperlipidemia with mild coronary artery stenosis may lead to a decrease in ADMA levels, which may contribute to improved endothelial function.

Vaspin Increases Nitric Oxide Bioavailability through the Reduction of Asymmetric Dimethylarginine in Vascular Endothelial Cells

Vaspin is an adipocytokine recently identified in the visceral adipose tissue of diabetic rats and having anti-diabetic effects. We have recently shown that vaspin has anti-atherogenic effect through Akt-mediated inhibition of endothelial cell apoptosis. Decreased activity of endothelial nitric oxide synthase (eNOS) plays an important role in the pathogenesis of atherosclerosis. Asymmetric dimethylarginine (ADMA) is a well-known endogenous competitive inhibitor of eNOS and risk factor of cardiovascular diseases. The aim of this study was to examine whether vaspin might protect against atherosclerosis through its beneficial effects on the ADMA-eNOS system. Treatment of vaspin significantly increased NO secretion from endothelial cells and isolated aorta from Sprague-Dawley (SD) rats. Furthermore, treatment of vaspin prevented fatty acid-induced decrease in endothelium-dependent vasorelaxation in isolated aorta of SD rat. For the mechanism of vaspin-induced NO biosynthesis, vaspin activated the STAT3 signaling pathway and stimulated eNOS phosphorylation (Ser 1177), a marker of eNOS activation, through STAT3-dependent mechanism. Furthermore, vaspin treatment increased the expression of dimethylarginine dimethylaminohydrolase (DDAH) II, the responsible enzyme for the degradation of ADMA, leading to a reduction in ADMA levels. Vaspin-induced increase in DDAH II gene expression was through STAT3-mediated stimulation of DDAH II promoter activity. These results suggest that vaspin increases eNOS activity by reducing ADMA level through STAT3-mediated regulation of DDAH II expression. Our findings provide a novel molecular mechanism of antiatherogenic actions of vaspin.

3,4,5,6-Tetrahydroxyxanthone preserves intercellular communication by reduction of the endogenous nitric oxide synthase inhibitor level

To observe the direct effects of 3,4,5,6-tetrahydroxyxanthone on connexin43 (Cx43) expression in cultured endothelial cells, cells were treated with lysophosphatidylcholine (LPC, 10 mg/l) for 24 h in the presence or absence of different concentrations of 3,4,5,6-tetrahydroxyxanthone (1, 3, or 10 μmol l− 1). The reactive oxygen species (ROS) production, cell viability, asymmetric dimethylarginine (ADMA) levels, and Cx43 expression were detected. 3,4,5,6-Tetrahydroxyxanthone significantly inhibited the increase in ROS production and ADMA level, increased cell viability and up-regulated Cx43 mRNA and protein expression induced by LPC. 3,4,5,6-Tetrahydroxyxanthone has protective effect in LPC-induced atherosclerotic lesions, which is at least partly related to the reduction of ADMA level and downregulation of Cx43 expression.

Effects of an EE/CA compared with EE/CA-metformin on serum ADMA levels in women with polycystic ovary syndrome

Abstract To determine the effects of EE/CA (Ethinylestradiol/ Cyproterone Acetate) and EE/CA-metformin treatments on the asymmetric dimethylarginine (ADMA) levels in women with PCOS (Polycystic Ovary Syndrome). Among 43 patients diagnosed with PCOS, one study arm (n=22) was administered (35 µg EE, 2mg CA) and the other (n=21) was administered (35 µg EE, 2mg CA plus 1700mg metformin). Serum ADMA, lipid profile, androgens, insulin, and HOMA-IR (Homeostatic Model Assessment of Insulin Resistance ) values were assessed prior to treatment and after 3 months of therapy. A significant reduction in ADMA levels relative to pre-treatment in the EE/CA+metformin group (1.2±0.4 vs 0.95±0.4, p=0.016) compared to the EE/CA group (1.0±0.5 vs 1.03±0.4, p >0.05). Andogens, insulin and HOMA-IR levels decreased in both treatment groups. All lipid profiles significantly improved in-group EE/CA+metformin while no significant decrease was observed in TG and HDL-cholesterol levels in EE/CA group. Post-treatment levels of HDL-C levels correlated significantly with the reducing ADMA levels in the EE/CA+metformin group (P=0.005, r= 0.602). Adding metformin to EE/CA therapy in PCOS may beneficial endothelium effects associated with reduction of ADMA levels.

Reduction of asymmetric dimethylarginine in the protective effects of rutaecarpine on gastric mucosal injury

Our recent study has shown that asymmetric dimethylarginine (ADMA) plays an important role in facilitating gastric mucosal injury by multiple factors. To explore whether the protection of rutaecarpine against gastric mucosal injury is related to reduction of ADMA content, a model of ethanol-induced gastric mucosal injury in rats was selected for this study. The ulcer index, the content of ADMA and NO, and the activity of dimethylarginine dimethylaminohydrolase (DDAH) in gastric tissues were measured in vivo after pretreatment with rutaecarpine. The in vitro effect of rutaecarpine on the release of calcitonin gene-related peptide (CGRP) and NO from isolated gastric tissues was also determined. The results showed that ethanol significantly increased the ulcer index, decreased the DDAH activity and the NO level, and elevated the ADMA level, which was attenuated by pretreatment with rutaecarpine (0.6 mg/kg or 1.2 mg/kg). In the isolated gastric tissues, rutaecarpine significantly increased the release of both CGRP and NO; the release of NO, but not CGRP, was abolished in the presence of l-NAME (10(-4) mol/L). The present results suggest that rutaecarpine protects the gastric mucosa against injury induced by ethanol and that the gastroprotection of rutaecarpine is related to reduction of ADMA levels through stimulating the release of CGRP.

Asymmetric dimethylarginine in end-stage renal disease patients: A biomarker modifiable by calcium blockade and angiotensin II antagonism?

The nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) is an emerging risk biomarker in cardiovascular and renal diseases. Apparently amlodipine and valsartan produce substantial reductions in the plasma concentration of this methylarginine in hemodialysis patients. These findings are of relevance for designing studies aimed at testing the etiologic relevance of ADMA to the high cardiovascular risk of ESRD.

Plasma markers of NO synthase activity in women after ovarian hyperstimulation: influence of estradiol on ADMA

The beneficial effects of estrogen on vasculature are partially explained by an estrogen-induced increase in nitric oxide (NO) synthesis. Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of NO synthase. In the present study, the effect of 17beta-estradiol (E2) on ADMA and NO synthesis was investigated both in vivo and in vitro. Plasma NO and ADMA levels were measured in healthy women at a low menstrual estrogenic stage (E2 < 100 pg/ml) and in women who were undergoing ovarian hyperstimulation (E2 > 2000 pg/ml) before in vitro fertilization embryo transfer. Primary human umbilical vein endothelial cell (HUVEC) cultures were incubated with and without 100 nM E2 for 24 hours and the NO and ADMA levels of the media were measured. A nitric oxide analyzer was used for the detection of NO metabolites. ADMA and L-arginine were measured by high-performance liquid chromatography after precolumn derivatization with o-phthaldialdehyde. The IVF patients with high plasma E2 concentrations had significantly lower (48%, n = 12) plasma ADMA and higher (56%, n = 14) NO levels than the women at a low estrogenic stage. The incubation of HUVEC cultures with estradiol resulted in a significant decrease (47%, n = 10) in ADMA and an increase (46%, n = 10) in NO concentration in the culture media. Estradiol, by reducing ADMA, may therefore facilitate NO synthesis in endothelial cells. The protective effects of estradiol on vasculature may partly be related to a reduction in ADMA levels.

Effect of fenofibrate on the level of asymmetric dimethylarginine in individuals with hypertriglyceridemia

To test whether treatment with fenofibrate decreases asymmetric dimethylarginine (ADMA) level in hypertriglyceridemic individuals. In the present study, 45 subjects with hypertriglyceridemia were recruited to receive treatment with fenofibrate (200 mg/d). Serum concentrations of ADMA, malondialdehyde (MDA), nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) were measured. Endothelial function assessed by flow-mediated dilation (FMD) of the brachial artery was performed. Compared with control, serum levels of ADMA (0.47+/-0.05 micromol/L in control and 0.62+/-0.28 micromol/L in hypertriglyceridemic patients, P<0.01), MDA and TNF-alpha were markedly elevated, and the level of NO was significantly reduced, concomitantly with impaired endothelium-dependent vasodilation in individuals with hypertriglyceridemia. 8-week treatment with fenofibrate significantly reduced the elevated levels of ADMA (0.53+/-0.12 micromol/L, P<0.01), MDA and TNF-alpha, attenuated the decreased level of NO and improved endothelial function. These results suggest that the beneficial effect of fenofibrate on the endothelium in hypertriglyceridemic individuals may be related to reduction of ADMA level.

Angiotensin-converting enzyme inhibitors prevent LDL-induced endothelial dysfunction by reduction of asymmetric dimethylarginine level

Angiotensin-converting enzyme inhibitors prevent LDL-induced endothelial dysfunction by reduction of asymmetric dimethylarginine level

Protective effects of daviditin A against endothelial damage induced by lysophosphatidylcholine.

Previous investigations have indicated that endogenous inhibitors of nitric oxide synthase (NOS) such as asymmetric dimethylarginine (ADMA) may play an important role in endothelium dysfunction, and some antioxidant drugs improve endothelium function via reduction of ADMA level. The present study examined the antioxidation and endothelial protection of daviditin A, a xanthone compound. Daviditin A significantly inhibited Cu(2+)-induced low-density lipoprotein (LDL) oxidation (EC50: 38.7 microM) and scavenged 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals (EC50: 57.5 microM). Vasodilator responses to acetylcholine in rings of the isolated thoracic aorta were impaired in the presence of lysophosphatidylcholine (LPC)(5 mg/l). Daviditin A (10 or 30 microM) significantly attenuated inhibition by LPC of endothelium-dependent relaxation. Incubation of ECV304 cells with LPC (5 mg/l) for 24 h markedly elevated lactate dehydrogenase (LDH) activity and the levels of malondialdehyde (MDA) and ADMA, and decreased the content of nitric oxide (NO) and the activity of dimethylarginine dimethylaminohydrolase (DDAH). Daviditin A (1, 3 or 10 microM) significantly attenuated the increased release of LDH, increased content of MDA, and decreased level of NO induced by LPC. Daviditin A (3 or 10 microM) significantly inhibited the increased concentration of ADMA. Daviditin A (10 microM) significantly attenuated the decreased activity of DDAH. The present results suggest that daviditin A preserves endothelial dysfunction elicited by LPC, and the protective effect of daviditin A on the endothelium is related to reduction of ADMA concentration.

The protective effects of monophosphoryl lipid A on the ischemic myocardium and endothelium in rats.

Previous investigations have shown that a single dose of low-density lipoprotein (LDL) injection causes a marked decrease in endothelium-dependent relaxation, and that endothelial dysfunction aggravates myocardial injury due to ischemia-reperfusion in atherosclerotic animals. Monophosphoryl lipid A-induced delayed preconditioning preserves the ischemic myocardium and endothelial cells. The objective of the present study was to examine the effect of monophosphoryl lipid A on endothelial function and ischemia-reperfusion-induced myocardial injury in the rats treated with LDL. A single injection of native LDL (4 mg/kg, i.v.) caused a significant decrease in vasodilator responses to acetylcholine and an increase in the serum level of asymmetric dimethylarginine, the endogenous nitric oxide synthase inhibitor. Pretreatment with monophosphoryl lipid A (300 or 450 microg/kg, i.p.) significantly improved endothelium-dependent relaxation and decreased concentrations of asymmetric dimethylarginine, and the effects of monophosphoryl lipid A were attenuated by L-nitro-arginine-methylester, but not by aminoguanidine. LDL treatment only aggravated the decreased coronary flows but did not affect cardiac dysfunction due to ischemia-reperfusion in the rats treated with LDL. Pretreatment with monophosphoryl lipid A significantly improved cardiac dysfunction by ischemia-reperfusion in the rats treated with or without LDL, an effect that was abolished by aminoguanidine. The present study suggests that: (1) a single injection of native LDL causes a decrease in endothelium-dependent relaxation, and aggravates the decrease of coronary flow due to ischemia-reperfusion, (2) pretreatment with monophosphoryl lipid A protects the myocardium against ischemia-reperfusion in the rats treated with or without native LDL, and (3) the protective effect of monophosphoryl lipid A on endothelial cells is related to reduction of asymmetric dimethylarginine level.