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Asymmetric Dimethylarginine: Clinical Applications in Pediatric Medicine

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Asymmetric Dimethylarginine: Clinical Applications in Pediatric Medicine View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector J Formos Med Assoc 2011;110(2):70–77 Contents lists available at ScienceDirect Volume 110 Number 2 February 2011 ISSN 0929 6646 Journal of the Journal of the Formosan Medical Association Formosan Medical Association Will conjugated pneumococcal vaccines with more serotypes and fewer doses work better? Asymmetric dimethylarginine: clinical applications in pediatric medicine Physician supply and demand in anatomical pathology in Taiwan Outcome of severe obsessive–compulsive disorder Formosan Medical Association Journal homepage: http://www.jfma-online.com Taipei, Taiwan Review Article Asymmetric Dimethylarginine: Clinical Applications in Pediatric Medicine You-Lin Tain,* Li-Tung Huang Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS). Growing evidence indicates that ADMA plays an important role in the initiation and progression of a variety of adulthood diseases, especially in the cardiovascular and renal systems. However, the study of ADMA in pediatric diseases has just begun. This review provides an overview of potential clinical applications of ADMA in pediatric practice, with an emphasis on the following areas: the biochemistry and pathophysiology of ADMA; clinical ramifications of elevated ADMA levels in pediatric population; age-related normal refer- ence ranges of ADMA; methodology for measuring ADMA; current and potential agents to reduce ADMA; and the problems that must be addressed before use of ADMA in pediatric medicine. ADMA will soon be available for use as a biomarker and therapeutic target in the pediatric population. Key Words: asymmetric dimethylarginine, dimethylarginine dimethylaminohydrolase, nitric oxide, pediatrics What is Asymmetric Dimethylarginine? ADMA is then released after proteolysis. Two other derivatives that are methylated by PRMTs Asymmetric dimethylarginine (ADMA) is a natu- are symmetric dimethylarginine (SDMA) and rally occurring amino acid that can inhibit the monomethylarginine (MMA). Peptidylarginine activity of nitric oxide synthase (NOS) to reduce deaminases can block methylation on the argi- NO production (Figure).1 Protein-incorporated nine residue within proteins by converting the ADMA is formed by post-translational methyla- arginine to citrulline.3 However, peptidylarginine tion, in which two methyl groups are placed on deaminases are not demethylases. The first argi- one of the terminal nitrogen atoms of the guani- nine demethylase, JMJD6, was recently identified dino group of arginine in proteins, by the pro- that can demethylate both protein-incorporated tein arginine methyltransferases (PRMTs).2 Free ADMA and SDMA.4 A healthy adult produces ©2011 Elsevier & Formosan Medical Association ................................................... Department of Pediatrics, Chang Gung Memorial Hospital–Kaohsiung Medical Center, Chang Gung University, College of Medicine, Taiwan. Received: March 30, 2010 *Correspondence to: Dr You-Lin Tain, Department of Pediatrics, Chang Gung Memorial Revised: May 31, 2010 Hospital, 123 Dabi Road, Niausung, Kaohsiung 833, Taiwan. Accepted: June 17, 2010 E-mail: [email protected] 70 J Formos Med Assoc | 2011 • Vol 110 • No 2 Asymmetric dimethylarginine in pediatrics 300 μmol (~60 mg) of ADMA per day.5 The other Why is the Study of ADMA Interesting? two derivatives are produced at 20–50% of the amount of ADMA.2 Free ADMA can be trans- ADMA is an endogenous NOS inhibitor. By in- ported in or out of cells via the cationic amino hibiting NO bioavailability, ADMA causes en- acid transporter family.6 Thus, excess circulating dothelial dysfunction, vasoconstriction, blood ADMA can be transported to major organs for pressure elevation, atherosclerosis, and kidney ADMA degradation, such as the kidney and liver. disease progression.7–11 A high prevalence of ele- Besides ADMA, other methylarginines also share vated plasma ADMA levels is observed in adults a common transport process with L-arginine. with hypercholesterolemia, hypertension, chronic Approximately 20% of ADMA is excreted by the kidney disease, diabetes mellitus, peripheral arte- kidneys into the urine, whereas 80% of ADMA rial disease, coronary artery disease, preeclampsia, is metabolized by the enzyme dimethylarginine heart failure, liver disease, stroke, and many dimethylaminohydrolase (DDAH) to citrulline other clinical disorders. The pathophysiological and dimethylamine.6 The biochemical pathways evidence of ADMA in these disorders is not related to ADMA are illustrated in the Figure. reviewed here because this has been reviewed Cell H2N N Any amino acid Protein N Arginine Type I–IV MMA PAD PRMT ADMA HO SDMA NH2 Type I Type II Citrulline O PRMT PRMT Proteolysis ADMA DDAH Citrulline +Dimethylamine ADMA L-MMA NO +Citrulline Arginine NOS CAT Circulation Inter-organ transport 20% Renal excretion Figure. Protein arginine methylation is performed by a family of enzymes named protein arginine methyltransferases (PRMTs), which methylate protein-incorporated L-arginine residues to generate protein-incorporated monomethylargi- nine (MMA). Type I PRMTs next convert MMA to asymmetric dimethylarginine (ADMA), and type II PRMTs generate symmetric dimethylarginine (SDMA). At the protein level, protein-incorporated L-arginine residues can be converted to citrulline by peptidylarginine deaminases, thereby blocking methylation on the arginine residue. Upon proteolytic cleav- age of arginine-methylated proteins, free MMA, ADMA, or SDMA is generated and released into the cytoplasm. Free L-arginine can be metabolized by nitric oxide synthase to NO and L-citrulline. By contrast, MMA and ADMA, but not SDMA, act as endogenous nitric oxide synthase inhibitors. In addition to L-arginine, free methylarginines can also be re- leased into the extracellular space by cationic amino acid transporter and transported to other organs or renally excreted. ADMA, but not SDMA, can be converted to L-citrulline and dimethylamine by dimethylarginine dimethylaminohydrolase. The structure of ADMA is shown in the upper middle portion of the figure. PAD = peptidylarginine deaminase; NOS = nitric oxide synthase; CAT = cationic amino acid transporter; DDAH = dimethylarginine dimethylaminohydrolase. J Formos Med Assoc | 2011 • Vol 110 • No 2 71 Y.L. Tain, L.T. Huang previously.5,9,11–15 The primary focus of this re- levels have been found in children and adolescents view is to summarize and discuss recent clinical with endothelial dysfunction, including hyper- and experimental evidence in which the possible tension,20 hypercholesterolemia,28 chronic kidney role of ADMA as a biomarker and therapeutic target disease,25 and diabetes mellitus.23 Unlike prospec- in the pediatric population has been assessed. tive data that indicate a direct and independent association between ADMA and cardiovascular endpoints in adult patients with different cardio- Is ADMA an Important Risk Marker in vascular diseases,12 pediatric studies have been Pediatric Diseases? limited by inadequate power and small sample size. Atherosclerosis manifests usually from mid- Prospective clinical studies have indicated a role dle age through a long preclinical stage, whereas for ADMA as a novel cardiovascular risk factor in endothelial dysfunction begins in childhood; various groups of adults, such as patients with therefore, the outcomes of ultimate importance hemodialysis,16 critically ill patients in the inten- in adults (e.g. death or cardiovascular events) sive care unit,17 and patients with coronary ar- rarely occur during childhood. It is noteworthy tery disease.18 In these studies, patients whose that ADMA levels are elevated in children with ADMA levels were within the highest quartile at congenital urea cycle disorders29 and in preterm the beginning of the study had 3–17-fold in- infants with mechanical ventilation.24 Instead of creased mortality compared with those with studying disorders that are characterized by ele- ADMA levels in the lowest quartile. Furthermore, vated ADMA levels in adulthood, pediatricians a 0.13-μM increase in ADMA was associated with might pay more attention to those diseases that a 21% increase in mortality risk in the general are common in children and adolescents. population.19 Thus, ADMA has been considered as a predictor of cardiovascular disease events and death in the adult population. Measurement of ADMA in Pediatric The list of clinical conditions in which elevated Populations ADMA levels are found in the pediatric population continues to grow (Table).20–30 Consistent with Heterogeneity is an unavoidable feature in pedi- the emergence of ADMA as a risk marker of car- atric studies. From birth to adolescence, numerous diovascular disease in adults,11 increased ADMA physiological changes occur in the body; for Table. Clinical conditions with elevated plasma ADMA levels in pediatric populations Condition % increase References from controls Hypertension 128 Goonasekera et al, 1997 [20] Congenital heart disease with pulmonary hypertension 160 Gorenflo et al, 2001 [21] Preterm infant 35 Mittermayer et al, 2006 [22] Type 1 diabetes mellitus 50 Altinova et al, 2007 [23] Preterm infant with mechanical ventilation 12 Richir et al, 2008 [24] Chronic kidney disease 38–200 Brooks et al, 2008 [25] Focal and segmental glomerulosclerosis 25 Lucke et al, 2008 [26] Arterial wall thickness ND Ayer et al, 2009 [27] Familial hypercholesterolemia 22 Jehlicka et al, 2009 [28] Argininosuccinate
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