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Asymmetric dimethylarginine Predicts One-year Recurrent Cardiovascular Events: Potential Biomarker of "Toxin Syndrome" in Coronary Heart Disease

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Chinese Journal of Integrative Medicine 2019年第5期25卷 327-333页

作者： XU Hao CHEN Zhuo SHANG Qing-hua GAO Zhu-ye YU Chang-an SHI Da-zhuo CHEN Ke-ji Cardiovascular Diseases Center Xiyuan HospitalChina Academy of Chinese Medical SciencesBeijing(100091)China Department of Cardiology China-Japan Friendship HospitalBeijing(100029)China

Objective: To examine the prognostic value of serum levels of asymmetric dimethylarginine(ADMA)in patients with stable coronary heart disease(CHD) thus explore a potential biomarker of "toxin syndrome" in CHD.Methods: In this prospective nested case-control study, 36 of 1,503 Chinese patients with stable CHD experienced at least 1 recurrent cardiovascular event(RCE) during 1-year fol ow-up. Serum levels of ADMA at the start of fol ow-up were compared between these 36 cases and 36 controls which matched to cases in terms of gender, age, history of hypertension, and myocardial infarction. Results: Based on the crude model, subjects in the 2 highest ADMA quartiles showed signi?cantly higher risk of developing RCE than those in the lowest ADMA quartile [odds ratio(OR) 4.09, 95%confidence interval(CI) 1.01 to 16.58; OR 6.76, 95% CI 1.57 to 29.07]. This association was also observed in the case-mix model(OR 5.51, 95% CI 1.23 to 24.61; OR 7.83, 95% CI 1.68 to 36.41) and multivariable model(OR 6.64,95% CI 1.40 to 31.49; OR 13.14, 95% CI 2.28 to 75.71) after adjusting for confounders. The multivariable model which combined ADMA and high-sensitivity C-reactive protein(hs CRP) showed better predictive power with areas under the receiver operator characteristic curves(0.779) than the model of either ADMA(0.694) or hs CRP(0.636). Conclusion:Serum ADMA level may be a potential biomarker of "toxin syndrome" in CHD which shows favorable prognostic value in predicting 1-year RCE in patients with stable CHD. [The registration number is Chi CTR-PRNRC-07000012]

关键词： asymmetric dimethylarginine recurrent cardiovascular event nested case-control study coronary heart disease toxin syndrome

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The role of L-arginine metabolism in neurocritical care patients

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Neural Regeneration Research 2022年第7期17卷 1446-1453页

作者： Marius Marc-Daniel Mader Patrick Czorlich Department of Neurosurgery University Medical Center Hamburg-EppendorfHamburgGermany Institute for Stem Cell Biology and Regenerative Medicine Stanford University School of MedicineStanfordCAUSA

Nitric oxide is an important mediator of vascular autoregulation and is involved in pathophysiological changes after acute neurological disorders.Nitric oxide is generated by nitric oxide synthases from the amino acid L-arginine.L-arginine can also serve as a substrate for arginases or lead to the generation of dimethylarginines,asymmetric dimethylarginine,and symmetric dimethylarginine,by methylation.Asymmetric dimethylarginine is an endogenous inhibitor of nitric oxide synthase and can lead to endothelial dysfunction.This review discusses the role of L-arginine metabolism in patients suffering from acute and critical neurological disorders often requiring neuro-intensive care treatment.Conditions addressed in this review include intracerebral hemorrhage,aneurysmal subarachnoid hemorrhage,and traumatic brain injury.Recent therapeutic advances in the field are described including current randomized controlled trials for traumatic brain injuries and hemorrhagic stroke.

关键词： arginine brain injuries,traumatic cerebral hemorrhage dimethylarginine nitric oxide stroke subarachnoid hemorrhage

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Asymmetric dimethylarginine as a mediator of vascular dysfunction in cirrhosis

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World Journal of Gastroenterology 2015年第32期21卷 9466-9475页

作者： Paloma Lluch Gloria Segarra Pascual Medina Department of Gastroenterology and Hepatology and Institute of Health Research INCLIVA Hospital Clínico Universitario Valencia Department of Physiology University of Valencia and Institute of Health Research INCLIVA Hospital Clínico Universitario Valencia

Cirrhosis is associated with marked abnormalities in the circulatory function that involve a reduction in systemic vascular resistance. An important cause of this vasodilatation is the increased production or activity of nitric oxide(NO) in the splanchnic circulation. During portal hypertension and cirrhosis an increased endothelial NO synthase(e NOS) activity is demonstrated in splanchnic vessels. In contrast, the activity of e NOS in the cirrhotic liver is decreased, which suggests a different regulation of e NOS in the liver and in the splanchnic vessels. Asymmetric dimethylarginine(ADMA) is an endogenous NO inhibitor and higher plasma levels of ADMA are related to increased cardiovascular risk in both the general population and among patients with cirrhosis. It has been demonstrated that the liver is a key player in the metabolism of ADMA. This observation was further supported by investigations in human patients, showing a close correlation between ADMA plasma levels and the degree of hepatic dysfunction. ADMA is degraded to citrulline and dimethylamine by dimethylarginine dimethylaminohydrolases(DDAHs). DDAHs are expressed as type 1 and 2 isoforms and are widely distributed in various organs and tissues, including the liver. In this review, we discuss experimental and clinical data that document the effects of dimethylarginines on vascular function in cirrhosis. Our increasing understanding of the routes of synthesis and metabolism of methylarginines is beginning to provide insights into novel mechanisms of liver disease and allowing us to identify potential therapeutic opportunities.

关键词： dimethylarginine dimethylaminohydrolase Nitric oxi

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Plasma Asymmetric dimethylarginine Levels in Neonates with Bronchopulmonary Dysplasia Associated with Pulmonary Hypertension

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Open Journal of Pediatrics 2018年第3期8卷 221-237页

作者： Safaa Abd Elhamid EL Meneza Seham Mohamed Bahgat Asmaa EL Saudi Nasr Department of Pediatrics Faculty of Medicine for Girls Al-Azhar University Cairo Egypt Clinical Pathology Department Faculty of Medicine for Girls Al-Azhar University Cairo Egypt

Background: Bronchopulmonary dysplasia (BPD) continues to be an important problem in neonates especially premature infants despite improved facilities of care, monitoring and treatment. Pulmonary hypertension (PH) is a major complicating factor and key cause of mortality in this population. Altered vascular and alveolar growth particularly in canalicular and early saccular stages of lung development following mechanical ventilation and oxygen therapy result in arrest of the lung development leading to BPD with PH. Early recognition of PH in infants with these risk factors is important for optimal management. We tested the hypothesis that asymmetric dimethylarginine, would be greater in infants with bronchopulmonary dysplasia associated pulmonary hypertension than in infants with BPD alone. The Aim: The aim of the current study was to measure the Asymmetric dimethylarginine (ADMA) levels, arginine levels & the plasma arginine-to-ADMA ratio in newborn infants with broncho-pulmonary dysplasia, to evaluate echocardiographic parameters among neonates with bronchopulmonary dysplasia, to correlate between plasma ADMA & arginine-to-ADMA ratio and echocardiographic (ECHO) parameters in those patients and to compare full term & preterm neonates with bronchopulmonary dysplasia as regard to plasma ADMA level. Methods: A case-control study was carried out of ninety (90) newborns selected from those admitted to Neonatal Intensive Care Unit at Maternity & Children Hospital and Alzhraa University hospital during the period from October 2015 to March 2018. Neonates were divided into 2 groups: Patient with BPD with PH (cases group): It included 45 neonates with BPD & PH, 35 preterm neonates and 10 full term neonates. Patient with BPD only (Control group): It included 45 neonates with BPD without PH. These 45 neonates were divided as 22 preterm neonates and 23 full term neonates. Laboratory work was done in Alzhraa University hospital. Asymmetric dimethylarginine (ADMA) levels & arginine levels were measured using competitive enzym

关键词： Asymmetric dimethylarginine Bronchopulmonary Dysplasia Pulmonary Hypertension

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Determination of Asymmetric dimethylarginine and Symmetric dimethylarginine in Biological Samples of Mice Using LC/MS/MS

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American Journal of Analytical Chemistry 2011年第3期2卷 303-313页

作者： Daisuke Saigusa Mai Takahashi Yoshitomi Kanemitsu Ayako Ishida Takaaki Abe Tohru Yamakuni Naoto Suzuki Yoshihisa Tomioka Laboratory of Oncology Pharmacy Practice and Sciences Graduate School of Pharmaceutical Sciences Tohoku University Sendai Japan

Herein, we present a novel method of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) determination within biological samples using protein precipitation and LC/MS/MS. Chromatographic separation of ADMA and SDMA was successfully performed using a silica column with optimized elution, or mobile phase, of 10 mM ammonium acetate buffer H2O/methanol/acetonitrile (20/30/45, v/v) at pH 4. The calibration ranges were 0.50 – 50.0 μg●mL-1, and good linearities were obtained for all compounds ( γ > 0.99). The intra- and inter-assay accuracies with recoveries and precisions at three concentration levels (i.e. 1.00, 5.00 and 25.0 μg●mL-1) were better than 86.9% and 7.36%, respectively. The analytical performance of the method was evaluated by determination of compounds in plasma, urine and tissues from male BALBc/J mice. For the first time, we were able to characterize the distribution of ADMA, SDMA and ADMA/SDMA in plasma, urine, brain, heart, kidneys, liver, lungs, pancreas and spleen. Additionally, we demonstrated that the ADMA/SDMA ratio in the brain was approximately 10-fold lower than all the other biological samples. Only 10 μL of plasma, 1 μL of urine and about 25 mg of tissues were required. These results suggest that the developed methodology was useful in ADMA and SDMA determination within biological samples.

关键词： Asymmetric dimethylarginine Symmetric dimethylarginine Creatinine Arginine Tissue Liquid Chromatography/Tandem Mass Spectrometry.

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Asymmetric dimethylarginine, a biomarker of cardiovascular complications in diabetes mellitus

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World Journal of Experimental Medicine 2015年第2期5卷 110-119页

作者： Hiroyuki Konya Masayuki Miuchi Kahori Satani Satoshi Matsutani Yuzo Yano Taku Tsunoda Takashi Ikawa Toshihiro Matsuo Fumihiro Ochi Yoshiki Kusunoki Masaru Tokuda Tomoyuki Katsuno Tomoya Hamaguchi Jun-ichiro Miyagawa Mitsuyoshi Namba Department of Internal Medicine Ashiya Municipal Hospital Division of Diabetes Endocrinology and Metabolism Department of Internal Medicine Hyogo College of Medicine Division of Innovative Diabetes Treatment Department of Internal Medicine Hyogo College of Medicine Center of Diabetes Therapy Department of Internal Medicine Itami City Hospital

Cardiovascular(CV) complications are an essential causal element of prospect in diabetes mellitus(DM), with carotid atherosclerosis being a common risk factor for prospective crisis of coronary artery diseases and/or cerebral infarction in DM subjects. From another point of view, asymmetric dimethylarginine(ADMA) has been established as an inhibitor of endogenous nitric oxide synthesis and the relationship between ADMA and arteriosclerosis has been reported. In our study with 87 type 2 DM(T2DM) patients, we have examined whether ADMA and other CV risk factors are the useful predictors of DMCV complications. After the measurement of the respective CV risk factors, we have followed the enrolled T2 DM patients for 5 years. We have finally analyzed 77 patients. DMCV complications developed in 15 cases newly within 5 years, and 4 cases recurred. The concentrations of ADMA in plasma were markedly more elevated in 19 DM patients with CV complications than in 58 DM patients without CV complications. Urinary albumin(U-Alb), mean intimal-medial thickness(IMT) and ankle brachial index(ABI) were also higher in patients with CV complications. Multiple regression analyses showed that U-Alb had an influence on the high level of ADMA(standardized β = 6.59, P = 0.00014) independently of age, systolic BP, fibrinogen, mean IMT, plaque score, and ABI. The review indicates what is presently known regarding plasma ADMA that might be a new and meaningful biomarker of CV complications in DM subjects.

关键词： Asymmetric dimethylarginine Biomarker Diabetes mellitus Cardiovascular complications Incretin

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Liver plays a central role in asymmetric dimethylargininemediated organ injury

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World Journal of Gastroenterology 2015年第17期21卷 5131-5137页

作者： Andrea Ferrigno Laura G Di Pasqua Clarissa Berardo Plinio Richelmi Mariapia Vairetti Department of Internal Medicine and Therapeutics University of Pavia27100 PaviaItaly

Asymmetric-dimethylarginine(ADMA) competes with L-arginine for each of the three isoforms of nitric oxide synthase:endothelial;neuronal;inducible.ADMA is synthesized by protein methyltransferases followed by proteolytic degradation.ADMA is metabolized to citrulline and dimethylamine,by dimethylarginine dimethylaminohydrolase(DDAH) and enters cells through cationic amino-acid transporters extensively expressed in the liver.The liver plays a crucial role in ADMA metabolism by DDAH-1 and,as has been recently demonstrated,it is also responsible for ADMA biliary excretion.A correlation has been demonstrated between plasma ADMA levels and the degree of hepatic dysfunction in patients suffering from liver diseases with varying aetiologies:plasma ADMA levels are increased in patients with liver cirrhosis,alcoholic hepatitis and acute liver failure.The mechanism by which liver dysfunction results in raised ADMA concentrations is probably due to impaired activity of DDAH due to severe inflammation,oxidative stress,and direct damage to DDAH.High plasma ADMA levels are also relevant as they are associated with the onset of multiorgan failure(MOF).Increased plasma concentration of ADMA was identified as an independent risk factor for MOF in critically-ill patients causing enhanced Intensive Care Unit mortality:a significant reduction in nitric oxide synthesis,leading to malperfusion in various organs,eventually culminating in multi organs dysfunction.

关键词： Liver Asymmetric dimethylarginine Nitricoxide Nitric oxide-synthase Multiple organ failure

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Endothelial dysfunction in cirrhosis: Role of inflammation and oxidative stress

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World Journal of Hepatology 2015年第3期7卷 443-459页

作者： Balasubramaniyan Vairappan Department of Biochemistry Jawaharlal Institute of Postgraduate Medical Education and Research

This review describes the recent developments in the pathobiology of endothelial dysfunction(ED) in the context of cirrhosis with portal hypertension and defines novel strategies and potential targets for therapy. ED has prognostic implications by predicting unfavourable early hepatic events and mortality in patients with portal hypertension and advanced liver diseases. EDcharacterised by an impaired bioactivity of nitric oxide(NO) within the hepatic circulation and is mainly due to decreased bioavailability of NO and accelerated degradation of NO with reactive oxygen species. Furthermore, elevated inflammatory markers also inhibit NO synthesis and causes ED in cirrhotic liver. Therefore, improvement of NO availability in the hepatic circulation can be beneficial for the improvement of endothelial dysfunction and associated portal hypertension in patients with cirrhosis. Furthermore, therapeutic agents that are identified in increasing NO bioavailability through improvement of hepatic endothelial nitric oxide synthase(e NOS) activity and reduction in hepatic asymmetric dimethylarginine, an endogenous modulator of e NOS and a key mediator of elevated intrahepatic vascular tone in cirrhosis would be interesting therapeutic approaches in patients with endothelial dysfunction and portal hypertension in advanced liver diseases.

关键词： Asymmetric dimethylarginine Endothelialfunction Nitric oxide Portal hypertension Hepaticcirrhosis, Reactive oxygen species Inflammation

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