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Genetic L-Arginine Deficiency and NO Insufficiency

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Genetic L-Arginine Deficiency and NO Insufficiency An experiment of nature: genetic l-arginine deficiency and NO insufficiency Joseph Loscalzo J Clin Invest. 2001;108(5):663-664. https://doi.org/10.1172/JCI13848. Commentary Nitric oxide (NO) is derived from the oxidation of the semiessential amino acid L-arginine by the NO synthases. Evidence supporting a central role for L-arginine in the NO synthase pathway comes from several observations. First, NO synthesis by cultured endothelial cells depends upon L-arginine content of the media (1). In addition, NO synthesis is blocked by L- arginine analogues (2), such as NG-monomethyl-L-arginine. Asymmetric dimethylarginine (ADMA), an endogenous compound known to inhibit NO synthases (3), and L-glutamine, which inhibits the generation of L-arginine from L-citrulline by argininosuccinate synthetase (4), also impair endothelial NO synthesis (5). Conversely, supplemental L-arginine improves endothelial function (6) and reverses endothelial dysfunction (7). In this issue of the JCI, Kamada and colleagues (8) report the results of vascular studies of an individual with a rare genetic disorder of L-arginine metabolism that lends further support to the critical role of L-arginine in NO synthesis. The authors describe a patient with a rare autosomal recessive disorder, lysinuric protein intolerance, characterized by a defect in dibasic amino acid transport caused by mutations in the SLC7A7 gene. The subject is a compound heterozygote carrying two different putative null alleles. The transporter is normally expressed in intestinal and renal epithelial cells, and deficient expression leads to impaired dietary uptake of exogenous L-arginine and impaired renal tubular reabsorption of filtered L-arginine. As a […] Find the latest version: https://jci.me/13848/pdf An experiment of nature: genetic L-arginine Commentary deficiency and NO insufficiency See related article, pages 717–724. Joseph Loscalzo Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, 700 Albany Street, W507, Boston, Massachusetts 02118, USA. Phone: (617) 638-4890; Fax: (617) 638-4066; E-mail: [email protected]. J. Clin. Invest. 108:663–664 (2001). DOI:10.1172/JCI200113848. Nitric oxide (NO) is derived from the tion in the patient is considerably lial NO synthesis and demonstrate that oxidation of the semiessential amino lower than normal (reduced by 79%). a naturally occurring deficiency of acid L-arginine by the NO synthases. In view of the effect of this genetic endothelial NO production is associat- Evidence supporting a central role for experiment of nature on plasma ed with endothelial dysfunction, mani- L-arginine in the NO synthase pathway L-arginine concentrations and the fest as abnormal vasomotor tone and a comes from several observations. First, importance of L-arginine on vascular prothrombotic state. Significantly, NO synthesis by cultured endothelial NO production, Kamada et al. replenishing the substrate by intra- cells depends upon L-arginine content assessed NO-dependent endothelial venous administration of L-arginine of the media (1). In addition, NO syn- function in this patient before and restores normal endothelial function. thesis is blocked by L-arginine ana- after intravenous L-arginine supple- These data support the view that logues (2), such as NG-monomethyl-L- mentation. They found that his endothelial NO derived from L-arginine arginine. Asymmetric dimethylarginine serum level of nitrogen oxides (NOx) maintains tissue perfusion by its (ADMA), an endogenous compound and his flow–mediated brachial artery vasodilator and antithrombotic effects. known to inhibit NO synthases (3), and vasodilator response were each L-glutamine, which inhibits the genera- approximately 70% lower than in con- Puzzles remaining tion of L-arginine from L-citrulline by trols. Intravenous infusion of L-argi- Several questions derive from these argininosuccinate synthetase (4), also nine caused an increase in NOx levels simple observations. First, why should impair endothelial NO synthesis (5). and restored normal flow–mediated a reduction of the plasma concentra- Conversely, supplemental L-arginine vasodilator responses in this patient, tion of L-arginine to this level lead to improves endothelial function (6) and whose coronary arteriogram was nor- reduced endothelial NO synthase reverses endothelial dysfunction (7). mal. Exercise treadmill testing and (eNOS) activity and NO production? In this issue of the JCI, Kamada and positron emission tomography (using The intracellular concentration of colleagues (8) report the results of vas- [13N]-ammonia) of the heart both L-arginine ranges from 100 µM to 2 cular studies of an individual with a showed evidence of myocardial mM in freshly isolated endothelial cells rare genetic disorder of L-arginine ischemia, which could be ameliorated (7), implying the existence of an extra- metabolism that lends further support by intravenous administration of cellular-to-intracellular concentration to the critical role of L-arginine in NO L-arginine. In addition to these abnor- gradient against which the L-arginine synthesis. The authors describe a malities in vasomotor function, an (y+) transporters drive L-arginine into patient with a rare autosomal recessive earlier report showed that this patient cells. Whether the reduced extracellular disorder, lysinuric protein intolerance, also had a reduced circulating platelet concentration of L-arginine in this characterized by a defect in dibasic count, increased plasma levels of the patient leads to less efficient cellular amino acid transport caused by muta- thrombin-antithrombin III complex, uptake is not known. Other factors tions in the SLC7A7 gene. The subject and elevated plasma fibrin(ogen) that influence the rate of L-arginine transport into endothelial cells, in addition to L-arginine concentration, include membrane potential, K+ con- These complementary clinical studies confirm that centration, other cationic amino acids endogenous L-arginine is essential for endothelial NO synthesis. (especially lysine and glutamine), and glucose and insulin concentrations (10). Most investigators believe that because the high-affinity cationic argi- is a compound heterozygote carrying degradation products. Importantly, nine transporter (CAT-1) colocalizes in two different putative null alleles. The intravenous L-arginine increased the caveolae with membrane-bound eNOS transporter is normally expressed in platelet count and reduced the levels (11), extracellular L-arginine concen- intestinal and renal epithelial cells, of thrombin-antithrombin III com- tration is the most important determi- and deficient expression leads to plex and fibrin(ogen) degradation nant of L-arginine availability for impaired dietary uptake of exogenous products (9), as well. eNOS. Since the plasma and assumed L-arginine and impaired renal tubular Taken together, these complementa- intracellular concentrations of L-argi- reabsorption of filtered L-arginine. As ry clinical studies confirm that endoge- nine in this patient still far exceed the a result, plasma L-arginine concentra- nous L-arginine is essential for endothe- KM for eNOS (2.9 µM for purified The Journal of Clinical Investigation | September 2001 | Volume 108 | Number 5 663 eNOS [ref. 12]), there should be no lopathy? If he made sufficient NO to Biophys. Res. Comm. 150:96–103. 3. Vallance, P., Leone, A., Calver, A., Collier, J., and substrate limitation for enzyme activi- prevent hypertension, why was this Moncada, S. 1992. Accumulation of an endoge- ty. Nevertheless, L-arginine infusion level of NO insufficient to impair nous inhibitor of nitric oxide synthesis in chron- clearly increases endothelial NO pro- thrombosis? Obviously, whatever the ic renal failure. Lancet. 339:572–575. 4. Sessa, W.C., Hecker, M., Mitchell, J.A., and Vane, duction in this patient, suggesting that flux of NO in this patient, it was inad- J.R. 1990. The metabolism of L-arginine and its the in vitro kinetic constants do not equate to limit thrombus formation. A significance for the biosynthesis of endotheli- apply in vivo, either because of com- growing body of data supports the um-derived relaxing factor: L-glutamine inhibits partmentalization of substrate and greater importance of endothelial NO the generation of L-arginine by cultured endothelial cells. Proc. Natl. Acad. Sci. USA. enzyme (in caveolae, for example), the as an inhibitor of platelet function and 87:8607–8611. presence of other uncharacterized fac- thrombosis than as a vasodilator (for 5. Hecker, M., Sessa, W.C., Harris, H.J., Anggard, tors that modulate enzyme function or review, see ref. 13). The endothelium is E.E., and Vane, J.R. 1990. The metabolism of L- arginine and its significance for the biosynthe- substrate availability, or both. not the only source of vascular NO sis of endothelium-derived relaxing factor: cul- Second, why is the patient not hyper- that serves an antithrombotic pur- tured endothelial cells recycle L-citrulline to tensive? The authors speculate that pose: platelet-derived NO limits L-arginine. Proc. Natl. Acad. Sci. USA. 87:8612–8616. there must be other compensatory recruitment of other platelets to the 6. Chin-Dusting, J.P.F., et al. 1996. Effects of in vasodilators that offset the loss of bioac- growing thrombus (14). In addition, vivo and in vitro L-arginine supplementation on tive NO in this patient, thus maintain- L-arginine suppresses tissue factor healthy human vessels. J. Cardiovasc. Pharm. 28:158–166. ing his blood pressure in the normal
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