Asymmetric Dimethylarginine: Clinical Applications in Pediatric Medicine

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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 reference 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

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]

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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 monomethylarginine (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 released 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.

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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 synthetase deficiency 177 Nagasaca et al, 2009 [29] Congenital portosystemic venous shunt 30 Nagasaca et al, 2010 [30]

ND = not determined.

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example, kidney function increases substantially ADMA levels in healthy adults might have been during the first 2 years of life. Given that 20% of due to age,31 race,32 body mass,32 or methodol- ADMA is excreted in the urine and renal function ogy.31 However, whether these factors influence is different from birth to adolescence, the ADMA ADMA levels in pediatric populations needs fur- level is greatly variable in pediatric populations ther investigation. due to the broad age range. In adults, plasma ADMA concentrations tend to increase with age, and the mean concentration for a healthy adult Intracellular ADMA in Experimental is between 0.4 μM and 0.6 μM.31 The distribution Disease Models of plasma ADMA levels among healthy, older adults (age > 60 years) ranges from 0.47 μM to At normal ranges of extracellular L-arginine and 0.85 μM; ADMA levels vary nearly twofold in the ADMA concentration, intracellular NOS is well geriatric population.32 In addition, the sex differ- saturated with its substrate L-arginine, which re- ence in ADMA concentrations is small in hu- sults in physiological production of NO. In the mans.31,33 By contrast, only a few of studies have presence of pathological concentrations of ADMA reported ADMA levels in neonates. Vida et al but physiological concentrations of L-arginine, have demonstrated that venous cord blood ADMA NOS activity decreases, which causes decreased levels are markedly elevated (∼1.06 μM) and fall NO production. Cellular ADMA levels can be significantly close to the normal adult levels by 5–20-fold higher than those in the plasma and postnatal day 2 (∼0.66 μM).34 In preterm infants, exist in a range that can inhibit NOS.6 Under such plasma ADMA level remains unchanged during conditions, the addition of exogenous L-arginine the first week of life but increases by the fourth displaces intracellular ADMA and restores the week, from 0.66 μM to 0.95 μM.35 During child- physiological L-arginine to ADMA ratio to a level hood, ADMA levels are higher than those in adults that preserves adequate NO production. Therefore, and diminish from birth until around 25 years of the state of activation or inhibition of NOS de- age, with a mean decrease of 15 nM per year.33,36 pends on the local intracellular concentration of Although ADMA levels are highest in neonatal L-arginine and ADMA, or the L-arginine/ADMA and geriatric populations, it remains to be deter- ratio. Although plasma ADMA levels increase in mined whether the U-shaped relationship between many patients with different disorders, intracel- normal ADMA levels and age can be attributed lular ADMA levels have not been well studied to renal function. under these circumstances. It is difficult to obtain Thus far, analytical techniques for the quanti- tissue samples from humans; therefore, animal tative determination of ADMA include high- models might prove to be advantageous for performance liquid chromatography (HPLC), studying intracellular ADMA regulation. gas chromatography–mass spectrometry (MS), gas There is very limited information regarding chromatography–tandem MS, liquid chromatog- intracellular ADMA levels in young diseased ani- raphy (LC)–MS, LC–tandem MS, and enzyme- mal models. We have found recently that plasma, linked immunosorbent assay. HPLC-based hepatic, and renal ADMA levels are increased in methods are the most widely used techniques for young rats 2 weeks after bile-duct ligation;37 a com- measuring ADMA in biological fluids such as monly used cholestatic liver disease model. The plasma, urine, and tissue homogenate. However, increase in circulating ADMA is probably caused enzyme-linked immunosorbent assay is not as by increased synthesis of ADMA (by increased reliable as currently available and validated HPLC- PRMT1 abundance) in the liver. Nevertheless, and LC–MS-based methods for detecting circu- the metabolism of ADMA appears unaltered lating ADMA.33 Differences observed among (represented by unaltered DDAH expression/ different studies for reported plasma (or serum) activity) in the damaged liver. By contrast, the

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decreased renal DDAH activity suggests that the with different insults, such as liver, kidney, and kidneys are unable to metabolize excess ADMA. cardiovascular injury.37–40 Alternatively, it is note- Unlike in the liver and kidneys, ADMA level in worthy that studying systemic and tissue ADMA the cerebral cortex of young bile duct ligation levels simultaneously is required to elucidate the rats is not changed.38 These findings highlight relative importance of different mechanisms that the importance of studying tissue instead of regulate ADMA homeostasis. plasma ADMA levels because the change in plasma Thus far, considerably less attention has been ADMA levels is not the equivalent of intracellu- paid to tissue than plasma ADMA levels in clini- lar ADMA levels in different tissues. In addition, cal practice, largely because of the lack of an ideal intracellular ADMA can be regulated differentially methodology. In addition, even though techniques in different tissues in the same disease model. used to assess tissue DDAH activity and expression In spontaneously hypertensive rats, a com- in experimental studies are well established,33,37,41 monly employed experimental model of hyper- clinical application is restricted due to the limited tension, plasma ADMA level is not significantly availability of samples. However, recent studies elevated, but renal ADMA concentration is higher have suggested that the plasma L-arginine/ than in control Wistar–Kyoto rats at 4 weeks of ADMA5 and urine ADMA/DMA (the metabolite age.39 With the development of hypertension, the of ADMA by DDAH) ratios might provide addi- plasma ADMA level is elevated in spontaneously tional useful clinical information.42 hypertensive rats at 12 and 24 weeks of age, which suggests that the accumulation of ADMA in the kidneys that precedes elevation of blood pres- How to Treat Elevated ADMA Levels? sure might play a role in the development of hypertension. To date, a specific ADMA-lowering agent remains In addition, the progressive increase in ADMA unavailable. Clinical studies have reported that levels in preterm infants suggests that ADMA par- treatment with metformin, oral contraceptives, ticipates in developmental programming of angiotensin-converting enzyme inhibitors, an- chronic adult diseases.30 In the offspring from a giotensin receptor blockers, fenofibrate, folic 50% maternal caloric restriction (CR) rat model, acid, and α-lipoic acid can lower plasma ADMA we found that plasma ADMA levels were elevated levels.43–52 Doubts remain whether the 10–24% nearly 30% in the CR group, whereas the renal decreases in plasma ADMA levels induced by these ADMA increases were not significant.40 Renal agents in different diseases are beneficial. Given DDAH (ADMA-metabolizing enzyme) activity was that intracellular ADMA levels are mainly regu- significantly increased in the CR group. Thus, it lated by PRMT and DDAH, specific PRMT in- is presumed that plasma ADMA increases observed hibitors or DDAH agonists might become novel with CR might be caused by excessive synthesis or therapeutic strategies. decreased metabolism of ADMA in extra-renal tis- First, because of the high degree of sequence sues. However, as a major organ of ADMA me- conservation across the PRMT family throughout tabolism, the kidney has increased DDAH activity evolution, creation of specific PRMT inhibitors is to metabolize excess circulating ADMA and main- difficult.2 In addition, because of the involvement tain a steady ADMA concentration. These findings of PRMT in complex cellular physiology, PRMT highlight that the regulation of intracellular ADMA inhibition might be fraught with unwanted side is complex, and the ability to maintain steady in- effects. However, a number of effective PRMT intracellular ADMA levels might protect the tissue hibitors await further experimental evaluation.53 against ADMA-induced damage. Second, recent advances in understanding the Conclusively, our data implicate the impor- regulation of DDAH enzymes might lead to sig- tance of ADMA in young diseased animal models nificant new therapeutic targets.54 Experimental

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studies have indicated that pravastatin, aminogua- normal reference ranges of ADMA and the nidine, pioglitazone, probucol, farnesoid X recep- methodology for measuring ADMA; (4) it dis- tor agonists, vitamin E, and melatonin can increase cusses the ever-accumulating body of data link- the activity and/or expression of DDAH, and ing agents to the reduction of ADMA levels, and thereby reduce ADMA levels.37,55–60 It needs to be new and interesting data on lowering ADMA in further evaluated whether there are inter-species experimental models; and (5) it indicates prob- differences in the renal handling of ADMA and lems that must be addressed before ADMA can whether ADMA-lowering therapy in experimental be used in pediatric medicine. animals can be translated successfully to humans, Basic and clinical research performed during especially in pediatric populations. the last 20 years has implicated ADMA as a novel cardiovascular risk factor, diagnostic marker, and therapeutic target in adult populations. Additional Are We Ready for ADMA in Pediatric studies exploring its role as a causal factor and as Practice? a target for drug development are warranted, especially in pediatric diseases. ADMA was first isolated and identified from human urine in 1970.61 Vallance et al first reported that ADMA acts as an endogenous NOS Acknowledgments inhibitor in 1992,1 and since then, ADMA has received considerable interest as a research topic.62 This work was supported by grant CMRPG890201 Circumstantial evidence suggests that ADMA plays from Chang Gung Memorial Hospital, grant NHRI- a crucial role in the initiation and progression of EX98-9826SC from National Health Research various diseases, especially in the cardiovascular Institutes, Taiwan, and grant NSC 98-2314-B- and renal systems in adults.8,9,54 However, the 182A-006-MY3 from National Science Council, study of ADMA in pediatric diseases remains a Taiwan. burgeoning field. The major blocks to future clinical application of ADMA in pediatric practice are as follows: References (1) plasma ADMA measurements in patients are not yet performed on a routine basis; (2) large, 1. Vallance P, Leone A, Calver A, et al. Accumulation of an prospective, multicenter collaborations are re- endogenous inhibitor of nitric oxide synthesis in chronic quired to conduct meaningful clinical research renal failure. Lancet 1992;339:572–5. 2. Bedford MT, Clarke SG. Protein arginine methylation in studies in children to prove that ADMA is a novel mammals: who, what, and why. Mol Cell 2009;33:1–13. risk factor in pediatric disorders; (3) measure- 3. Raijmakers R, Zendman AJ, Egberts WV, et al. Methylation ment of ADMA for age- or size-related hetero- of arginine residues interferes with citrullination by peptidyl- geneity needs normalization; (4) indices that arginine deiminases in vitro. J Mol Biol 2007;367:1118–29. represent intracellular ADMA levels from experi- 4. Chang B, Chen Y, Zhao Y, et al. JMJD6 is a histone arginine demethylase. Science 2007;318:444–7. mental models are required for clinical transla- 5. Bode-Böger SM, Scalera F, Ignarro LJ. The L-arginine par- tion; and (5) specific ADMA-lowering agents still adox: importance of the L-arginine/asymmetrical dimethyl- require investigation. arginine ratio. Pharmacol Ther 2007;114:295–306. In conclusion, this review provides an overview 6. Teerlink T, Luo Z, Palm F, et al. Cellular ADMA: regulation of clinical applications of ADMA, with an empha- and action. Pharmacol Res 2009;60:448–60. 7. Cooke JP. Does ADMA cause endothelial dysfunction? sis on pediatric populations: (1) it discusses the Arterioscler Thromb Vasc Biol 2000;20:2032–7. biochemistry and pathophysiology of ADMA; 8. Vallance P, Leiper J. Cardiovascular biology of the asymmetric (2) it presents a list of pediatric diseases with dimethylarginine: dimethylarginine dimethylaminohydrolase elevated ADMA levels; (3) it presents age-related pathway. Arterioscler Thromb Vasc Biol 2004;24:1023–30.

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