Am J Physiol Lung Cell Mol Physiol 292: L15–L17, 2007;
doi:10.1152/ajplung.00322.2006.
Editorial Focus
The lung in the balance: arginine, methylated arginines, and nitric oxide
Raed A. Dweik
Departments of Pulmonary, Allergy, and Critical Care Medicine, and Pathobiology, Cleveland Clinic, Cleveland, Ohio
Address 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]).
http://www.ajplung.org
thesis 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).
It 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 Larginine 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.
1040-0605/07 $8.00 Copyright © 2007 the American Physiological Society
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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, syn-
Editorial Focus
L16
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.
relates 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.
GRANTS
R. A. Dweik is supported by National Heart, Lung, and Blood Institute
Grant HL-68863.
REFERENCES
Fig. 1. Chemical structure of L-arginine and endogenous methylarginines.
L-NMMA, NG-monomethylarginine; SDMA, symmetric NGNG-dimethylarginine; ADMA, asymmetric NGNG-dimethylarginine.
AJP-Lung Cell Mol Physiol • VOL
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Both intracellular (0.1–1 mM) and extracellular (73–150 ␮M)
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Editorial Focus
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