The lung in the balance: arginine, methylated arginines, and nitric oxide

Abstract

EDITORIAL FOCUSThe lung in the balance: arginine, methylated arginines, and nitric oxideRaed A. DweikRaed A. DweikPublished Online:01 Jan 2007https://doi.org/10.1152/ajplung.00322.2006This is the final version - click for previous versionMoreSectionsPDF (100 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat the lung is a major source of nitric oxide (NO), be it from nitric oxide synthase (NOS) III in the endothelium of the vast pulmonary circulation, NOS II in the epithelium of the large surface area of the airways, or NOS I in the nonadrenergic noncholinergic nerves (6). NO produced in the lung has major roles in lung physiology, including airway and vascular smooth muscle relaxation, ventilation perfusion matching, neurotransmission, host defense and bacteriostasis, mucociliary clearance, and airway mucus secretion (12). It is also involved in the pathobiology of different lung diseases including asthma and pulmonary hypertension (4–7, 12). Furthermore, as a highly diffusible molecule with strong affinity to hemoglobin, NO produced in the lung is avidly taken up by the blood in the pulmonary circulation and transported throughout the body, serving physiological functions well beyond the lungs and the pulmonary circulation (8, 16, 18). The report from Bulau et al., one of the current articles in focus (Ref. 3, see p. L18 in this issue), reports another remarkable related discovery: the lung is also a major source of the endogenous NOS inhibitor asymmetric NGNG-dimethylarginine (ADMA). This finding has significant physiological and pathological implications not only for the pulmonary circulation and the lung but also for the systemic circulation and beyond.The discovery in the late 1980s that endothelial derived relaxing factor was NO (9, 14) shifted the attention of the scientific community on arginine from its traditional role in protein synthesis to its role as a precursor for the production of NO (19). Although NO has long been known as an atmospheric pollutant present in vehicle exhaust emissions, smog, and cigarette smoke, it was also used as a pharmacological agent known to activate guanylate cyclase and produce cGMP (1). However, the discovery that this simple gaseous molecule is endogenously produced was certainly a paradigm shift at the time that led to an exponential growth in our knowledge about NO and its role in human physiology and disease. Interestingly enough, NG-monomethylarginine (l-NMMA), a pharmacological inhibitor of NOS that was used to study the function of NO (13), turned out to be a naturally occurring compound as well (21). Along with other methylated arginines, l-NMMA is the product of protein degradation and release of methylated arginine, bringing the story back full circle with the focus again on arginine not only as a precursor of NO but also as the precursor of methylated arginines through protein synthesis, posttranslational modification, and finally degradation.Arginine or 2-amino-5-guanidinovaleric acid (Fig. 1) is a semiessential amino acid. Young mammals require arginine exogenously, whereas adults can synthesize it de novo. Arginine participates in various metabolic pathways including cleavage (via arginase) into urea and ornithine in the urea cycle, deamination (via arginine deaminase) to citrulline, synthesis of creatine (via arginine-glycine amidinotransferase and guanidinoacetate N-methyltransferase), synthesis of proteins [where it can be methylated via protein arginine methyltransferases (PRMT)], and as a precursor for the synthesis of NO (via NOS) (19). Although the arginine-NO pathway only represents a fraction of the total arginine metabolism, it has attracted considerable attention due to the many versatile roles that NO plays in almost all organ systems. In addition to activating guanylate cyclase resulting in smooth muscle relaxation, NO is also involved in a variety of physiological functions (12).Fig. 1.Chemical structure of l-arginine and endogenous methylarginines. l-NMMA, NG-monomethylarginine; SDMA, symmetric NGNG-dimethylarginine; ADMA, asymmetric NGNG-dimethylarginine.Download figureDownload PowerPointIt is currently well accepted that the lung plays a major role in NO metabolism and is well established as a major source of NO. Interestingly, in this issue, Bulau et al. (3) demonstrate that the lung is also a major source of the NOS inhibitor and arginine analog ADMA. They demonstrated that the lung expresses the enzymes necessary for methylarginine formation (type I PRMT) as well as clearance [dimethylarginine dimethylaminohydrolase (DDAH) 1]. PRMT expression correlated with enhanced protein arginine methylation. Furthermore, bronchoalveolar lavage fluid and serum exhibited almost identical levels of ADMA/symmetric NGNG-dimethylarginine (SDMA), suggesting that methylarginine metabolism by the lung significantly contributes to circulating levels of ADMA.ADMA is one of three circulating endogenous methylated analogs of l-arginine (Fig. 1) that are produced as a result of proteolysis of methylated proteins. Methylation of arginine incorporated in proteins is a process of posttranslational modification of protein function (similar to phosphorylation) that is carried out by a group of enzymes known as the PRMT enzymes. Several subtypes of PRMTs have been identified as being responsible for methylation of protein arginine residues by the addition of one or two methyl groups to the guanidine nitrogen atoms of arginine. Methylated arginines are products of subsequent protein degradation. The two asymmetric methylarginines, l-NMMA and ADMA, act as false substrates and competitively inhibit NOS activity, blocking the formation of endogenous NO (19, 20). SDMA does not inhibit NOS, and whereas l-NMMA is frequently used as a pharmacological inhibitor of NOS, its low circulating levels makes it unlikely to contribute significantly to NOS inhibition in vivo. This makes ADMA the major endogenous NOS inhibitor among the methylated arginines (20). Asymmetric methylarginines (l-NMMA and ADMA) can be hydrolyzed by DDAH to yield citrulline and mono- or dimethylamine (11). DDAH does not hydrolyze SDMA. By competitively inhibiting NO synthesis from l-arginine by NOS (Fig. 2), the asymmetric endogenous methylarginines can have significant biological effects encompassing all the negative effects of “NO deficiency.” Thus methylated arginines may be responsible (at least in part) for a peculiar concept in NO metabolism known as the “l-arginine paradox.” It refers to the phenomenon that exogenous arginine causes NO-mediated effects despite the fact that, at physiological state, NOS is already saturated with arginine and its activity should not be affected by increasing arginine concentration. Both intracellular (0.1–1 mM) and extracellular (73–150 μM) arginine concentrations far exceed the apparent Km (the half-saturating arginine concentration) of all NOSs (e.g., 2.9 μM for endothelial NOS) (19). Despite this, elevating plasma arginine levels enhance systemic and vascular NO production in a dose-dependent manner suggesting some form of competitive inhibition of NOS that could be overcome with increasing arginine concentrations (19). This paradox is not fully understood, but several theories have been put forth to explain it based on our current understanding of arginine and NO metabolism (19) including: the compartmentalization of arginine in the cytoplasm (extracellular arginine may be preferentially utilized by NOS within this microenvironment); the inhibitory effects of l-citrulline (cells may need extra arginine to compete with citrulline); and competition from arginase for arginine (a substrate for both enzymes) making less arginine available for NO production by NOS. This concept could also be explained by the presence of ADMA, which competitively antagonizes arginine and which could also be overcome with increasing arginine concentrations.Fig. 2.Nitric oxide synthase (NOS)-arginine-ADMA. Nitric oxide (NO) is formed from arginine by various NOS. ADMA is produced as a result of degradation of methylated proteins. It competes with arginine and blocks NO production by acting as a false substrate for NOS. ADMA is partially cleared by the kidney, but the major route of clearance is metabolic action by dimethylarginine dimethylaminohydrolase (DDAH). DDAH function may be inhibited by various pathological processes resulting in accumulation of ADMA, which has the functional effect of “NO deficiency.” CAD, coronary artery disease; DM, diabetes mellitus; HTN, systemic hypertension; PAH, pulmonary arterial hypertension.Download figureDownload PowerPointOverall, it appears that the synthesis and metabolism of endogenous methylarginines are highly regulated. Imbalance in this pathway is associated with several pathobiological consequences. Since elevated plasma levels were first reported in patients with renal failure (21), ADMA has been implicated in the pathogenesis of a variety of clinical conditions such as systemic hypertension, pulmonary hypertension, stroke, diabetes, hyperlipidemia, hyperhomocyst(e)inemia, and atherosclerosis, and the list is constantly expanding (11, 17, 19, 20). More recently, ADMA has been shown to be a risk factor for cardiovascular disease (2). The lung seems to play a prominent role in this important and delicate balance. One particular lung disease where this balance is perturbed is pulmonary hypertension, a group of diseases characterized by high pulmonary artery pressures and pulmonary vascular resistance. Patients with pulmonary hypertension have low levels of NO in their exhaled breath, and the severity of the disease inversely correlates with NO reaction products in the lung (4, 10). Interestingly, patients with pulmonary hypertension also have elevated ADMA levels (15, 22) and evidence of peripheral vascular dysfunction as well (16).The current report by Bulau et al. (3) and the rapidly accumulating research in the arginine-methylarginine-NO field predict a central role for the lung in our efforts to understand this area in biology as well as the pathobiological implications and consequences of abnormalities in this important metabolic pathway. As a major source of not only NO but also the NOS inhibitor ADMA, the lung likely plays a critical role in the delicate balance of NOS enzyme activity and NO production in the whole body. It is only fitting that the lung, which has two separate circulations and receives a higher blood flow than any other organ in the body, plays such a major homeostatic role.GRANTSR. A. Dweik is supported by National Heart, Lung, and Blood Institute Grant HL-68863.REFERENCES1 Arnold WP, Mittal CK, Katsuki S, Murad F. Nitric oxide activates guanylate cyclase and increases guanosine 3′:5′-cyclic monophosphate levels in various tissue preparations. Proc Natl Acad Sci USA 74: 3203–3207, 1977.Crossref | PubMed | ISI | Google Scholar2 Boger RH, Cooke JP, Vallance P. ADMA: an emerging cardiovascular risk factor. Vasc Med 10, Suppl1: S1–S2, 2005.ISI | Google Scholar3 Bulau P, Zakrzewicz D, Kitowska K, Leiper J, Gunther A, Grimminger F, Eickelberg O. Analysis of methylarginine metabolism in the cardiovascular system identifies the lung as a major source of ADMA. Am J Physiol Lung Cell Mol Physiol 292: L18–L24, 2007.Link | ISI | Google Scholar4 Dweik RA. Pulmonary hypertension and the search for the selective pulmonary vasodilator. Lancet 360: 886–887, 2002.Crossref | PubMed | ISI | Google Scholar5 Dweik RA, Comhair SA, Gaston B, Thunnissen FB, Farver C, Thomassen MJ, Kavuru M, Hammel J, Abu-Soud HM, Erzurum SC. NO chemical events in the human airway during the immediate and late antigen-induced asthmatic response. Proc Natl Acad Sci USA 98: 2622–2627, 2001.Crossref | PubMed | ISI | Google Scholar6 Dweik RA, Laskowski D, Abu-Soud HM, Kaneko F, Hutte R, Stuehr DJ, Erzurum SC. Nitric oxide synthesis in the lung. Regulation by oxygen through a kinetic mechanism. J Clin Invest 101: 660–666, 1998.Crossref | PubMed | ISI | Google Scholar7 Ghamra ZW, Dweik RA. Primary pulmonary hypertension: an overview of epidemiology and pathogenesis. Cleve Clin J Med 70, Suppl1: S2–S8, 2003.Google Scholar8 Gladwin MT, Shelhamer JH, Schechter AN, Pease-Fye ME, Waclawiw MA, Panza JA, Ognibene FP, Cannon RO 3rd. Role of circulating nitrite and S-nitrosohemoglobin in the regulation of regional blood flow in humans. Proc Natl Acad Sci USA 97: 11482–11487, 2000.Crossref | PubMed | ISI | Google Scholar9 Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA 84: 9265–9269, 1987.Crossref | PubMed | ISI | Google Scholar10 Kaneko FT, Arroliga AC, Dweik RA, Comhair SA, Laskowski D, Oppedisano R, Thomassen MJ, Erzurum SC. Biochemical reaction products of nitric oxide as quantitative markers of primary pulmonary hypertension. Am J Respir Crit Care Med 158: 917–923, 1998.Crossref | PubMed | ISI | Google Scholar11 Ogawa T, Kimoto M, Sasaoka K. Purification and properties of a new enzyme, NG,NG-dimethylarginine dimethylaminohydrolase, from rat kidney. J Biol Chem 264: 10205–10209, 1989.Crossref | PubMed | ISI | Google Scholar12 Ozkan M, Dweik RA. Nitric oxide and airway reactivity. Clin Pulm Med 8: 199–206, 2001.Crossref | Google Scholar13 Palmer RM, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from l-arginine. Nature 333: 664–666, 1988.Crossref | PubMed | ISI | Google Scholar14 Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327: 524–526, 1987.Crossref | PubMed | ISI | Google Scholar15 Pullamsetti S, Kiss L, Ghofrani HA, Voswinckel R, Haredza P, Klepetko W, Aigner C, Fink L, Muyal JP, Weissmann N, Grimminger F, Seeger W, Schermuly RT. Increased levels and reduced catabolism of asymmetric and symmetric dimethylarginines in pulmonary hypertension. FASEB J 19: 1175–1177, 2005.Crossref | PubMed | ISI | Google Scholar16 Pyle J, Duncan JM, Dweik RA. Exhaled nitric oxide levels may predict variability in peripheral forearm blood flow. Am J Respir Crit Care Med 169: A394, 2004.Google Scholar17 Smith CL, Birdsey GM, Anthony S, Arrigoni FI, Leiper JM, Vallance P. Dimethylarginine dimethylaminohydrolase activity modulates ADMA levels, VEGF expression, and cell phenotype. Biochem Biophys Res Commun 308: 984–989, 2003.Crossref | PubMed | ISI | Google Scholar18 Stamler JS, Jia L, Eu JP, McMahon TJ, Demchenko IT, Bonaventura J, Gernert K, Piantadosi CA. Blood flow regulation by S-nitrosohemoglobin in the physiological oxygen gradient. Science 276: 2034–2037, 1997.Crossref | PubMed | ISI | Google Scholar19 Sy BMC, Dweik EE, Dweik RA. Arginine and nitric oxide. In: Modern Nutrition in Health and Disease (10th ed.), edited by Shils ME, Shike M, Ross AC, Caballero B, and Cousins RJ. Philadelphia, PA: Lippincott Williams & Wilkins, 2005.Google Scholar20 Tran CT, Leiper JM, Vallance P. The DDAH/ADMA/NOS pathway. Atheroscler Suppl 4: 33–40, 2003.PubMed | ISI | Google Scholar21 Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 339: 572–575, 1992.Crossref | PubMed | ISI | Google Scholar22 Xu W, Kaneko FT, Zheng S, Comhair SA, Janocha AJ, Goggans T, Thunnissen FB, Farver C, Hazen SL, Jennings C, Dweik RA, Arroliga AC, Erzurum SC. Increased arginase II and decreased NO synthesis in endothelial cells of patients with pulmonary arterial hypertension. FASEB J 18: 1746–1748, 2004.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: R. A. Dweik, Pulmonary Vascular Program, Dept. of Pulmonary, Allergy, and Critical Care Medicine, Cleveland Clinic, 9500 Euclid Ave./A90, Cleveland, OH 44195 (e-mail: [email protected]) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Collections Cited ByCan ADMA play a role in determining pulmonary hypertension related to chronic obstructive pulmonary disease?11 August 2017 | The Clinical Respiratory Journal, Vol. 12, No. 4Metabolomics based predictive biomarker model of ARDS: A systemic measure of clinical hypoxemia2 November 2017 | PLOS ONE, Vol. 12, No. 11Increased ADMA levels are associated with poor pulmonary outcome in preterm neonates8 June 2016 | The Journal of Maternal-Fetal & Neonatal Medicine, Vol. 30, No. 7Assessment of the Effects of Renal Impairment and Smoking on the Pharmacokinetics of a Single Oral Dose of the Soluble Guanylate Cyclase Stimulator Riociguat (BAY 63-2521)1 March 2016 | Pulmonary Circulation, Vol. 6, No. 1_supplThe Vaccine Candidate Substrate Binding Protein SBP2 Plays a Key Role in Arginine Uptake, Which Is Required for Growth of Moraxella catarrhalis23 November 2015 | Infection and Immunity, Vol. 84, No. 2Enhanced production of nitric oxide in A549 cells through activation of TRPA1 ion channel by cold stressNitric Oxide, Vol. 40Exhaled Nitric Oxide as a Biomarker in COPD and Related ComorbiditiesBioMed Research International, Vol. 2014Nitric Oxide Deficiency in Pulmonary Hypertension: Pathobiology and Implications for Therapy1 January 2013 | Pulmonary Circulation, Vol. 3, No. 1Protein Arginine Methyltransferases (PRMTs): Promising Targets for the Treatment of Pulmonary Disorders27 September 2012 | International Journal of Molecular Sciences, Vol. 13, No. 12Online trapping and enrichment ultra performance liquid chromatography–tandem mass spectrometry method for sensitive measurement of “arginine-asymmetric dimethylarginine cycle” biomarkers in human exhaled breath condensateAnalytica Chimica Acta, Vol. 754Breath biomarkers in diagnosis of pulmonary diseasesClinica Chimica Acta, Vol. 413, No. 21-22Cardiovascular Biomarkers in Exhaled BreathProgress in Cardiovascular Diseases, Vol. 55, No. 1Exhaled nitric oxide (F E NO) in non-pulmonary diseases2 May 2012 | Journal of Breath Research, Vol. 6, No. 2Nitric oxide and asthma severity: towards a better understanding of asthma phenotypes20 April 2012 | Clinical & Experimental Allergy, Vol. 42, No. 5Update on exhaled nitric oxide in pulmonary disease9 January 2014 | Expert Review of Respiratory Medicine, Vol. 6, No. 1Rosuvastatin attenuates monocrotaline-induced pulmonary hypertension via regulation of Akt/eNOS signaling and asymmetric dimethylarginine metabolismEuropean Journal of Pharmacology, Vol. 666, No. 1-3An Official ATS Clinical Practice Guideline: Interpretation of Exhaled Nitric Oxide Levels (F eNO ) for Clinical ApplicationsAmerican Journal of Respiratory and Critical Care Medicine, Vol. 184, No. 5Serum Asymmetric Dimethylarginine, Nitrate, Vitamin B 12 , and Homocysteine Levels in Individuals with Pulmonary EmbolismMediators of Inflammation, Vol. 2011Lung Injury Biomarkers3 November 2010Exhaled Nitric Oxide in Pulmonary DiseasesChest, Vol. 138, No. 3Redox Control of Asthma: Molecular Mechanisms and Therapeutic OpportunitiesAntioxidants & Redox Signaling, Vol. 12, No. 1From arginine methylation to ADMA: A novel mechanism with therapeutic potential in chronic lung diseases29 January 2009 | BMC Pulmonary Medicine, Vol. 9, No. 1Paracrine purinergic signaling determines lung endothelial nitric oxide productionRainer Kiefmann, Mohammad N. 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Schwiebert1 January 2007 | American Journal of Physiology-Renal Physiology, Vol. 292, No. 1 Press Release E-cigarette Use during Pregnancy Creates Lung Dysfunction in Babies - December 8, 2022 More from this issue > Volume 292Issue 1January 2007Pages L15-L17 Copyright & PermissionsCopyright © 2007 the American Physiological Societyhttps://doi.org/10.1152/ajplung.00322.2006PubMed16980373History Published online 1 January 2007 Published in print 1 January 2007 Metrics