Brief Review

Does ADMA Cause Endothelial Dysfunction?

John P. Cooke
https://doi.org/10.1161/01.ATV.20.9.2032
Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:2032-2037
Originally published September 1, 2000

Jump to

Abstract

Abstract—Asymmetric dimethylarginine (ADMA) is an endogenous and competitive inhibitor of nitric oxide synthase. Plasma levels of this inhibitor are elevated in patients with atherosclerosis and in those with risk factors for atherosclerosis. In these patients, plasma ADMA levels are correlated with the severity of endothelial dysfunction and atherosclerosis. By inhibiting the production of nitric oxide, ADMA may impair blood flow, accelerate atherogenesis, and interfere with angiogenesis. ADMA may be a novel risk factor for vascular disease.

  • Received May 5, 2000.
  • Accepted June 1, 2000.

NO and Vascular Homeostasis

Endothelium-derived nitric oxide (NO) is the most potent endogenous vasodilator known, exerting its effect via stimulation of soluble guanylate cyclase to produce cyclic GMP.1 2 3 NO is a critical modulator of blood flow and blood pressure.4 5 6 7 It is released by the endothelium in response to shear stress and plays an important role in flow-mediated vasodilation.4 5 Endothelial release of NO opposes the vasoconstrictor effects of norepinephrine, endothelin, angiotensin II, and serotonin.8 Pharmacological inhibition or a genetic deficiency of endothelial NO synthase (NOS) impairs endothelium-dependent vasodilation and increases vascular resistance.6 7 8 9 In patients with coronary artery disease, an impairment of NO activity may contribute to ischemic syndromes.10 11

Vascular NO also influences vascular structure. NO suppresses the proliferation of vascular smooth muscle.12 A chronic deficiency or loss of NO activity may contribute to medial thickening and/or myointimal hyperplasia.13 14 Conversely, treatment with NO donors or gene therapy with NOS reduces lesion formation after vascular injury in animal models.15 16 Furthermore, NO inhibits the interaction of circulating blood elements with the vessel wall. Platelet aggregation and leukocyte adherence are unlikely when the endothelium is healthy.17 18 19 The loss of NO activity accelerates the development of vascular lesions.20 21 A loss of NO activity occurs early in the course of human vascular disease22 23 and is a contributing factor to abnormal vasomotion and ischemic symptoms.10 11 In addition, there is accumulating evidence that the deficit of NO participates in the initiation and progression of atherosclerosis. Intriguingly, very recent data indicate that defective endothelial vasodilator function is predictive of vascular events.24 Accordingly, there is a compelling clinical rationale to understand the mechanisms of endothelial dysfunction.

Endothelial Dysfunction Is Multifactorial

The mechanisms of endothelial vasodilator dysfunction are multifactorial and dependent on the nature of the vascular disorder. Because of the multifactorial nature of endothelial dysfunction, therapy targeted at restoring endothelial function must be informed by an understanding of the pathophysiology. Endothelial vasodilator dysfunction may be due to increased vasoconstrictor and/or reduced vasodilator influence. Of the causes of reduced vasodilator influence, derangements of the NOS pathway have been most studied. Derangements of the NOS pathway may be categorized as reductions in (1) NO half-life, (2) sensitivity to NO, (3) NOS expression, or (4) NOS activity. Experimental evidence exists for each of these mechanisms.

Increased vascular elaboration of superoxide anion is an abnormality commonly associated with atherosclerosis and its risk factors.25 The half-life of NO is reduced under conditions of oxidative stress.26 The attendant formation of peroxynitrite anion produces lipid peroxidation and nitrosation of tyrosine moieties, thereby disrupting cell membranes, cell signaling, and cell survival.27 Conversely, antioxidant strategies lengthen NO half-life, increase NOS expression, and restore endothelial vasodilator function.28 29 30 The oxidative enzymes responsible for increased oxidative stress in the vessel wall include NAD(P)H oxidase, xanthine oxidase, and NOS itself. Under conditions of reduced availability of l-arginine (the NO precursor) or tetrahydrobiopterin (an NOS cofactor), the preferred substrate of the monomer is oxygen, producing superoxide anion.31 32 33 34 35 Antioxidants may enhance the activity of NOS by preserving tetrahydrobiopterin.36

In the later stages of atherosclerosis, reduced sensitivity to endogenous and exogenous NO is observed, possibly due to oxidative inactivation of NO and/or soluble guanylate cyclase. In addition, in advanced atherosclerosis, reduced expression of the endothelial isoform of the NOS enzyme is observed, possibly due to cytokine- or lipid-induced instability and/or reduced transcription of NOS mRNA.37 38 Additionally, certain polymorphisms of the NOS gene may be associated with functional alterations in the enzyme and vascular disease.39 Finally, a growing body of data indicates that endogenous inhibitors of NOS may be responsible for endothelial vasodilator dysfunction in many individuals with coronary and peripheral arterial diseases and in those with their risk factors, particularly hypercholesterolemia, hyperhomocysteinemia, tobacco use, and aging. The endogenous inhibitors are asymmetric dimethylarginine (ADMA) and N-monomethylarginine (NMA). Because the former is the predominant species (plasma levels of ADMA are 10-fold greater than those of NMA), further discussion will focus on ADMA.

ADMA Is an Endogenous Inhibitor of NOS

It has long been known to biochemists that methylated arginines are excreted in the urine.40 However, Vallance et al41 recognized the physiological significance of this observation and were the first to demonstrate that endogenous ADMA antagonized endothelium-dependent vasodilation. They observed a 9-fold elevation of plasma ADMA in patients with renal failure. Intriguingly, plasma from patients with renal failure induced vasoconstriction of vascular rings in vitro, an effect that was reversed by the addition of l-arginine to the medium. The marked elevation in plasma ADMA may explain the severe endothelial impairment of patients with renal failure. In these patients, dialysis normalizes ADMA levels, an effect that is temporally related to an improvement in endothelium-dependent vasodilation.42 43 Administration of l-arginine to patients with renal failure also restores endothelial function.43

Subsequently, plasma ADMA has been found to be elevated in patients with vascular disease, as well as in the setting of risk factors for vascular disease.44 45 46 47 48 49 Hypercholesterolemic animals and humans manifest an impairment of endothelium-dependent vasodilation.49 50 51 In these individuals, plasma ADMA levels are better correlated with endothelial dysfunction than are LDL cholesterol levels.49 Furthermore, the endothelial vasodilator dysfunction associated with an elevated plasma ADMA level is reversible by administration of l-arginine, consistent with the notion that ADMA is a competitive inhibitor.49

Intriguingly, plasma levels of ADMA appear to be dynamically regulated and can be correlated with measures of NO synthesis. In the Dahl salt-sensitive rat, a high-salt diet is associated with an increase in urinary ADMA excretion and an increase in blood pressure.52 In humans with salt-sensitive hypertension, administration of a high-salt diet increases plasma ADMA levels and blood pressure and reduces urinary NOx; a low-salt diet reverses these abnormalities.46 Preliminary studies indicate that plasma ADMA also increases with administration of a high-fat diet, which is associated with a temporally related impairment in endothelial vasodilator dysfunction.53 The mechanisms by which ADMA becomes elevated under these conditions require an understanding of its origin and metabolic fate.

Origin and Fate of ADMA

ADMA is not derived from the methylation of free l-arginine. Rather, ADMA is derived from the catabolism of proteins containing methylated arginine residues (Figure 1⇓). These proteins are largely found in the nucleus and appear to be involved in RNA processing and transcriptional control.55 There are 2 types of enzymes that methylate arginine residues. These are protein arginine methyltransferase types I and II (PRMT I and PRMT II).56 57 PRMT type I forms ADMA and NMA, whereas PRMT type II forms symmetric dimethylarginine (SDMA) and NMA. SDMA does not inhibit NOS. There are a number of type I PRMTs, with specificity for different proteins.55 By contrast, the only known substrate for type II PRMT is myelin basic protein.

Figure 1.
Figure 1.

Metabolism of ADMA. Methylated arginines are derived from the breakdown of proteins that have been acted on by enzymes known as PRMTs. PRMT type I methylates proteins that, when hydrolyzed, release ADMA and NMA. PRMT type II methylates proteins that, when hydrolyzed, release SDMA and NMA. DPT is expressed in the kidney and can utilize ADMA, NMA, or SDMA.92 Acetylated derivatives of methylated arginines have been found in human urine, but the pathways responsible have not been delineated. Light arrows refer to minor metabolic pathways. Heavy arrows refer to major pathways.

When these proteins undergo hydrolysis, their methylated arginine residues are released. Methylated arginines are excreted in the urine.40 This explains the increase in plasma ADMA levels in patients with renal insufficiency. Methylated arginines may also be metabolized. A minor source of metabolism occurs via dimethylarginine pyruvate transferase in the kidney and possibly, via acetylation in the liver. However, the major metabolic pathway for NMA and ADMA is the enzyme dimethylarginine dimethylaminohydrolase (DDAH).58 Two isoforms of DDAH are known, I and II. Either or both isoforms have been found in every cell type examined. DDAH I is typically found in tissues expressing neuronal NOS, whereas DDAH II predominates in tissues containing the endothelial isoform of NOS.59

Dysregulation of DDAH: A Novel Mechanism of Endothelial Dysfunction

DDAH plays an important role in regulating ADMA levels. When SDMA is injected intravenously, 60% is recovered in the urine; by contrast, after intravenous administration, only 5% of ADMA is recovered in the urine.60 Furthermore, in renal failure, there is a significantly greater increase in plasma SDMA than in ADMA.61 These observations are explained by the fact that ADMA, but not SDMA, is a substrate for DDAH.58 ADMA undergoes extensive metabolism in vivo compared with SDMA.

Additional evidence that DDAH is a critical regulator of ADMA levels comes from observations of the effects of the DDAH inhibitor 4124W. Addition of 4124W to an isolated vascular segment induces gradual vasoconstriction, which is reversed by addition of l-arginine to the medium.62 This finding is most consistent with the view that ADMA is constantly being produced in the course of normal protein turnover. The production of ADMA is balanced by its metabolism by DDAH. Accordingly, inhibition of DDAH activity will cause a gradual accumulation of ADMA, sufficient to induce vasoconstriction.

Recent data from our laboratory indicate that hypercholesterolemia may cause a decline in DDAH activity. The accumulation of ADMA that ensues may contribute to lipid-induced endothelial vasodilator dysfunction. We found that when cultured endothelial cells were exposed to oxidized LDL cholesterol, ADMA accumulated in the medium at a faster rate than when cells were treated with vehicle or native LDL cholesterol.63 The accelerated accumulation of ADMA was associated with a temporally related decline in DDAH activity. Similarly, the activity of DDAH is reduced in both vascular and nonvascular tissues of hypercholesterolemic rabbits (in which the animals’ plasma ADMA levels are known to be elevated).63 More recently, we have made similar observations in vitro and in vivo regarding the adverse effect of hyperglycemia to reduce DDAH activity and to increase ADMA accumulation (J.P.C. et al, unpublished observations, 2000). Furthermore, the decline in DDAH activity appears to be related to oxidative stress and can be prevented by the use of antioxidants.

Does ADMA Explain the Arginine Paradox?

The “arginine paradox” refers to the discordance between observations made in vitro and those made in vivo regarding the sensitivity of NO synthesis to arginine availability. Studies of a partially purified preparation of NOS in a cell-free system indicated that the Km of NOS for l-arginine was in the micromolar range.64 Accordingly, l-arginine should not be rate-limiting for NO synthesis because it is in the 50 micromolar range in plasma and in the millimolar range within the endothelial cell. Indeed, in normal animals and humans, most investigators report no effect of l-arginine on endothelial vasodilator function. Yet under certain circumstances, l-arginine does seem to be rate-limiting. This is most apparent in animal models or in patients with hypercholesterolemia and/or atherosclerosis, wherein endothelium-dependent vasodilation is impaired. There is a high degree of concordance among investigators that under these conditions, administration of l-arginine improves endothelium-dependent vasodilation and increases NO synthesis.49 65 66 67 68 69 70 71 Moreover, l-arginine relieves symptoms and improves exercise tolerance in patients with coronary and peripheral arterial disease. Indeed, the weight of the evidence indicates that there is a nutritional requirement for supplemental l-arginine in these individuals.

The elevation of plasma ADMA provides a possible explanation for the benefits of supplemental l-arginine in these patients. The plasma level of ADMA is normally ≈1 μmol/L, is typically increased 2-fold in subjects with risk factors for vascular disease, and is increased even further (up to 10-fold) in patients with clinical atherosclerosis. But with circulating l-arginine levels at ≈50 μmol/L, is this elevation in ADMA sufficient to have an effect on NOS? Perhaps the sensitivity to ADMA could be explained by the fact that it also competes with l-arginine for uptake by the y+ transporter. Furthermore, the y+ transporter and endothelial NOS are physically associated in the caveolae of endothelial cells.72 The arginine interventions discussed above certainly support the view that NO synthesis is sensitive to changes in extracellular arginine availability. Furthermore, Faraci and colleagues73 have shown that the Km of NOS isolated from the cerebellum (largely neuronal NOS) is 2.8 μmol/L. Also, concentrations of 1 to 10 μmol/L ADMA were sufficient to cause modest contractions of cerebral vessels in situ.

Intravenous infusion of ADMA sufficient to increase plasma concentrations 9-fold increased systolic blood pressure by 15% in anesthetized guinea pigs.41 Intra-arterial infusion of ADMA (8 μmol/min) reduced forearm blood flow by ≈30% in healthy volunteers.41 Finally, we have observed intriguing changes in endothelial behavior when cultured cells are chronically exposed to concentrations of ADMA and l-arginine similar to those found in the plasma of hypercholesterolemic individuals. ADMA-exposed cells increase the adhesiveness of monocytes in coculture.74 Furthermore, monocytes and T lymphocytes derived from hypercholesterolemic individuals are hyperadhesive, an abnormality that is reversed by several weeks of oral administration of l-arginine.74 This finding is consistent with previous observations in hypercholesterolemic animal models and humans that administration of the NO precursor inhibits endothelial-monocyte interaction.18 75 76 These observations raise the following question.

Is ADMA a Risk Factor for Vascular Disease?

Preclinical studies suggest that NO is a potent, endogenous, antiatherogenic molecule, suppressing key processes in atherosclerosis. This view is supported by the fact that pharmacological inhibition or a genetic deficiency of endothelial NOS accelerates atherogenesis in animal models.20 21 77 Does endogenous ADMA accelerate atherosclerosis? Our earlier observations that chronic administration of l-arginine can slow and even reverse the progression of vascular lesions are consistent with this hypothesis.78 79 80 81 82 83 84 85 86 The hypothesis is further supported by the observation that supplemental dietary arginine enhances NO synthesis in the rabbit aorta, as measured directly by chemiluminescence.18

Intriguingly, in animal models and in humans, endogenous ADMA levels may be predictive of vascular lesion formation. After balloon injury, the regenerating endothelial cells manifest higher intracellular levels of ADMA and impaired endothelium-dependent vasodilation.87 88 89 The severity of the endothelial dysfunction and the intracellular levels of ADMA are directly related to the intimal thickness of the injured vessel.87 89 There are similar data for humans. In 120 Japanese individuals with varying levels of risk, intimal-medial thickness of the carotid artery was measured by ultrasound and was correlated with blood pressure, lipid profile, smoking history, blood sugar, age, and ADMA. A multivariate analysis revealed that ADMA and age were the only independent predictors in these patients.90

Finally, 3 groups have independently offered evidence that endothelial vasodilator dysfunction is an independent predictor of vascular events.24 91 92 Impaired coronary blood flow response to acetylcholine or reduced brachial artery response to flow was predictive of vascular morbidity and mortality. To the extent that ADMA is responsible for the impairment of endothelial vasodilator dysfunction in these patients, it may be a predictor for vascular events.

Future Directions

Work in this area would be facilitated by an improved assay. Currently, detection of ADMA is labor-intensive and requires its derivatization to a fluorescent probe, followed by high-pressure liquid chromatography combined with a fluorescent detector. High-throughput and reproducible assays are needed and may arise as immunoassays or enzymatic assays. These assays will facilitate determination of the clinical significance of ADMA as a contributor to pathophysiology and symptoms and as a risk factor for vascular events.

The regulation of DDAH is just beginning to be understood, and modulators of its expression are being defined. Structure-function studies and novel drug discovery will be enhanced by obtaining its crystal structure. Genetically engineered animals that overexpress or are deficient in DDAH are being created and will provide new insights into the developmental and physiological actions of DDAH. Other enzymes along the metabolic pathway of ADMA deserve further scrutiny; for example, can increased methylation of specific proteins or increased catabolism of these proteins be involved in elevation of plasma ADMA?

Other interesting biological questions remain to be answered. Does ADMA play an important regulatory role in inflammation or infection (ie, as a “brake” on the action of inducible NOS)? Does ADMA have a role in the central or peripheral nervous system? Are other processes that are modulated by NO (eg, angiogenesis) affected by endogenous ADMA? There are many unanswered questions, but it seems certain that endogenous NOS inhibitors represent an important new class of biological mediators. An understanding of their physiological and pathological roles and their regulation may lead to new therapeutic avenues.

Acknowledgments

This work was supported in part by a grant from the National Heart, Lung, and Blood Institute (RO1 HL58638) and funding from the Tobacco Related Diseases Research Program. Dr Cooke is an Established Investigator of the American Heart Association.

References

  1. ↵
    Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288:373–376.
    OpenUrlCrossRefPubMed
  2. ↵
    Ignarro LJ, Burke TM, Wood KS, Wolin MS, Kadowitz PJ. Association between cyclic GMP accumulation and acetylcholine-elicited relaxation of bovine intrapulmonary artery. J Pharmacol Exp Ther. 1984;228:682–690.
    OpenUrlAbstract/FREE Full Text
  3. ↵
    Murad F. The 1996 Albert Lasker Medical Research Awards: signal transduction using nitric oxide and cyclic guanosine monophosphate. JAMA. 1996;276:1189–1192.
    OpenUrlCrossRefPubMed
  4. ↵
    Pohl U, Holtz J, Busse R, Bassenge E. Crucial role of endothelium in the vasodilator response to increased flow in vivo. Hypertension. 1986;8:37–44.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    Cooke JP, Rossitch E Jr, Andon NA, Loscalzo J, Dzau VJ. Flow activates an endothelial potassium channel to release an endogenous nitrovasodilator. J Clin Invest. 1991;88:1663–1671.
  6. ↵
    Rees DD, Palmer RMJ, Moncada S. Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc Natl Acad Sci U S A. 1989;86:3375–3378.
    OpenUrlAbstract/FREE Full Text
  7. ↵
    Vallance P, Collier J, Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet. 1989;2:997–1000.
    OpenUrlPubMed
  8. ↵
    Cooke JP, Dzau VJ. Nitric oxide synthase: role in the genesis of vascular disease. Annu Rev Med. 1997;48:489–509.
    OpenUrlCrossRefPubMed
  9. ↵
    Huang PL, Hyang Z, Mashimo H, Block KD, Moskowitz MA, Bevan JA, Fishman MC. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature. 1995;377:239–242.
    OpenUrlCrossRefPubMed
  10. ↵
    Ludmer PL, Selwyn AP, Shook TL, Wayne RR, Mudge GH, Alexander RW, Ganz P. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med. 1986;315:1046–1051.
    OpenUrlCrossRefPubMed
  11. ↵
    Nabel EG, Selwyn AP, Ganz P. Large coronary arteries in humans are responsive to changing blood flow: an endothelium-dependent mechanism that fails in patients with atherosclerosis. J Am Coll Cardiol.. 1990;16:349–356.
    OpenUrlCrossRefPubMed
  12. ↵
    Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromocyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest. 1989;83:1774–1777.
  13. ↵
    Numaguchi K, Egashira K, Takemoto M, Kadokami T, Shimokawa H, Sueishi K, Takeshita A. Chronic inhibition of nitric oxide synthesis causes coronary microvascular remodeling in rats. Hypertension. 1995;26(pt 1):957–962.
  14. ↵
    Weidinger FF, McLenachan JM, Cybulsky M, Gordon JM, Rennke HA, Hollenberg NK, Ganz P, Cooke JP. Persistent dysfunction of regenerated endothelium following balloon angioplasty of rabbit iliac artery. Circulation. 1990;81:1667–1679.
    OpenUrlAbstract/FREE Full Text
  15. ↵
    von der Leyen HE, Gibbons GH, Morishita R, Lewis NP, Zhang L, Nakajima M, Kaneda Y, Cooke JP, Dzau VJ. Gene therapy inhibiting neointimal vascular lesion: in vivo transfer of endothelial cell nitric oxide synthase gene. Proc Natl Acad Sci U S A. 1995;92:1137–1141.
    OpenUrlAbstract/FREE Full Text
  16. ↵
    Le Tourneau T, Van Belle E, Corseaux D, Vallet B, Lebuffe G, Dupuis B, Lablanche JM, McFadden E, Bauters C, Bertrand ME. Role of nitric oxide in restenosis after experimental balloon angioplasty in the hypercholesterolemic rabbit: effects on neointimal hyperplasia and vascular remodeling. J Am Coll Cardiol. 1999;33:876–882.
    OpenUrlCrossRefPubMed
  17. ↵
    Stamler JS, Mendelsohn ME, Amarante P, Smick D, Andon N, Davies PF, Cooke JP, Loscalzo J. N-Acetylcysteine potentiates platelet inhibition by endothelium-derived relaxing factor. Circ Res. 1989;65:789–795.
    OpenUrlAbstract/FREE Full Text
  18. ↵
    Tsao P, McEvoy LM, Drexler H, Butcher EC, Cooke JP. Enhanced endothelial adhesiveness in hypercholesterolemia is attenuated by l-arginine. Circulation. 1994;89:2176–2182.
    OpenUrlAbstract/FREE Full Text
  19. ↵
    Tsao P, Theilmeier G, Singer AH, Leung LL, Cooke JP. l-Arginine attenuates platelet reactivity in hypercholesterolemic rabbits. Arterioscler Thromb. 1994;14:1529–1533.
    OpenUrlAbstract/FREE Full Text
  20. ↵
    Cayatte AJ, Palacino JJ, Horten K, Cohen RA. Chronic inhibition of nitric oxide production accelerates neointima formation and impairs endothelial function in hypercholesterolemic rabbits. Arterioscler Thromb. 1994;14:753–759.
    OpenUrlAbstract/FREE Full Text
  21. ↵
    Naruse K, Shimizu K, Muramatsu M, Toki Y, Miyazaki Y, Okumura K, Hashimoto H, Ito T. Long-term inhibition of NO synthesis promotes atherosclerosis in the hypercholesterolemic rabbit thoracic aorta: PGH2 does not contribute to impaired endothelium-dependent relaxation. Arterioscler Thromb. 1994;14:746–752.
    OpenUrlAbstract/FREE Full Text
  22. ↵
    Creager MA, Cooke JP, Mendelsohn ME, Gallagher SJ, Coleman SM, Loscalzo J, Dzau VJ. Impaired vasodilatation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest. 1990;86:228–234.
  23. ↵
    Celermajer DS, Sorensen KE, Bull C, Robinson J, Deanfield JE. Endothelium-dependent dilation in the systemic arteries of asymptomatic subjects related to coronary risk factors and their interaction. J Am Coll Cardiol. 1994;24:1468–1474.
    OpenUrlCrossRefPubMed
  24. ↵
    Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR Jr, Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation.. 2000;101:948–954.
    OpenUrlAbstract/FREE Full Text
  25. ↵
    Ohara Y, Petersen TE, Harrison DG. Hypercholesterolemia increases endothelial superoxide anion production. J Clin Invest.. 1993;91:2546–2551.
  26. ↵
    Rubanyi GM, Vanhoutte PM. Superoxide anions and hyperoxia inactivate endothelium-derived relaxing factor. Am J Physiol. 1986;250(pt 2):H822–H87.
  27. ↵
    Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and the ugly. Am J Physiol.. 1996;271:C1424–C1437.
    OpenUrlAbstract/FREE Full Text
  28. ↵
    Mügge A, Elwell JH, Peterson TE, Hofmeyer TG, Heistad DD, Harrison DG. Chronic treatment with polyethylene-glycolated superoxide dismutase partially restores endothelium-dependent vascular relaxations in cholesterol-fed rabbits. Circ Res. 1991;69:1293–1300.
    OpenUrlAbstract/FREE Full Text
  29. ↵
    Gokce N, Keaney JF Jr, Frei B, Holbrook M, Olesiak M, Zachariah BJ, Leeuwenburgh C, Heinecke JW, Vita JA. Long-term ascorbic acid administration reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation. 1999;99:3234–3240.
    OpenUrlAbstract/FREE Full Text
  30. ↵
    Ramasamy S, Drummond GR, Ahn J, Storek M, Pohl J, Parthasarathy S, Harrison DG. Modulation of expression of endothelial nitric oxide synthase by nordihydroguaiaretic acid, a phenolic antioxidant in cultured endothelial cells. Mol Pharmacol. 1999;56:116–123.
    OpenUrlAbstract/FREE Full Text
  31. ↵
    Pou S, Pou WS, Bredt DS, Snyder SH, Rosen GM. Generation of superoxide by purified brain nitric oxide synthase. J Biol Chem. 1992;267:24173–24176.
    OpenUrlAbstract/FREE Full Text
  32. ↵
    Stroes E, Kastelein J, Cosentino F, Erkelens W, Wever R, Koomans H, Lüscher T, Rabelink T. Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. J Clin Invest.. 1997;99:41–46.
    OpenUrlCrossRef
  33. ↵
    Xia Y, Tsai AL, Berka V, Zweier JL. Superoxide generation from endothelial nitric-oxide synthase: a Ca2+/calmodulin-dependent and tetrahydrobiopterin regulatory process. J Biol Chem. 1998;273:25804–25808.
    OpenUrlAbstract/FREE Full Text
  34. ↵
    Pritchard KA Jr, Groszek L, Smalley DM, Sessa WC, Wu M, Villalon P, Wolin MS, Stemerman MB. Native low-density lipoprotein increases endothelial cell nitric oxide synthase generation of superoxide anion. Circ Res. 1995;77:510–518.
    OpenUrlAbstract/FREE Full Text
  35. ↵
    Vasquez-Vivar J, Kalyanaraman B, Martasek P, Hogg N, Masters BS, Karoui H, Tordo P, Pritchard KA Jr. Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors. Proc Natl Acad Sci U S A. 1998;95:9220–9225.
    OpenUrlAbstract/FREE Full Text
  36. ↵
    Huang A, Vita JA, Venema RC, Keaney J. Ascorbic acid enhances endothelial nitric oxide synthase activity by increasing intracellular tetrahydrobiopterin. J Biol Chem. 2000;275:17399–17406.
    OpenUrlAbstract/FREE Full Text
  37. ↵
    Oemar BS, Tschudi MR, Godoy N, Brovkovich V, Malinski T, Luscher TF. Reduced endothelial nitric oxide synthase expression and production in human atherosclerosis. Circulation. 1998;97:2494–2498.
    OpenUrlAbstract/FREE Full Text
  38. ↵
    Liao JK, Shin WS, Lee WY, Clark SL. Oxidized low-density lipoprotein decreases the expression of endothelial nitric oxide synthase. J Biol Chem. 1995;270:319–324.
    OpenUrlAbstract/FREE Full Text
  39. ↵
    Hingorani AD, Liang CF, Fatibene J, Lyon A, Monteith S, Parsons A, Haydock S, Hopper RV, Stephens NG, O’Shaughnessy KM, Brown MJ. A common variant of the endothelial nitric oxide synthase (Glu298→Asp) is a major risk factor for coronary artery disease in the UK. Circulation. 1999;100:1515–1520.
    OpenUrlAbstract/FREE Full Text
  40. ↵
    Kakimoto Y, Akazawa S. Isolation and identification of NG, NG-, and NG, N′G-dimethyl-arginine, N-mono-, di-, and trimethyllysine, and glucosylgalactosyl-, and galactosyl-δ-hydroxylysine from human urine. J Biol Chem. 1970;245:5751–5758.
    OpenUrlAbstract/FREE Full Text
  41. ↵
    Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet.. 1992;339:572–575.
    OpenUrlCrossRefPubMed
  42. ↵
    Kielstein J, Böger R, Bode-Böger S, Schäffer J, Barbey M, Koch K, Frölich J. Asymmetric dimethylarginine plasma concentrations differ in patients with end-stage renal disease: relationship to treatment method and atherosclerotic disease. J Am Soc Nephrol. 1999;10:594–600.
    OpenUrlAbstract/FREE Full Text
  43. ↵
    Hand MF, Haynes WG, Webb DJ. Hemodialysis and l-arginine, but not d-arginine, correct renal failure-associated endothelial dysfunction. Kidney Int. 1998;53:1068–1077.
    OpenUrlCrossRefPubMed
  44. ↵
    Boger RH, Bode-Boger SM, Thiele W, Junker W, Alexander K, Frolich JC. Biochemical evidence for impaired nitric oxide synthesis in patients with peripheral arterial occlusive disease. Circulation. 1997;95:2068–2074.
    OpenUrlAbstract/FREE Full Text
  45. ↵
    Usui M, Matsuoka H, Miyazaki H, Ueda S, Okuda S, Imaizumi T. Increased endogenous nitric oxide synthase inhibitor in patients with congestive heart failure. Life Sci. 1998;62:2425–2430.
    OpenUrlCrossRefPubMed
  46. ↵
    Fujiwara N, Osanai T, Kamada T, Katoh T, Takahashi K, Okumura K. Study on the relationship between plasma nitrite and nitrate level and salt sensitivity in human hypertension: modulation of nitric oxide synthesis by salt intake. Circulation. 2000;101:856–861.
    OpenUrlAbstract/FREE Full Text
  47. ↵
    Holden D, Fickling S, Whitley G, Nussey S. Plasma concentrations of asymmetric dimethylarginine, a natural inhibitor of nitric oxide synthase, in normal pregnancy and preeclampsia. Am J Obstet Gynecol. 1998;178:551–556.
    OpenUrlCrossRefPubMed
  48. ↵
    Surdacki S, Nowicki M, Sandmann J, Tsikas D, Boeger R, Bode-Boeger S, Kruszelnicka-Kwiatkowska O, Kokot F, Dubiel J, Froelich J. Reduced urinary excretion of nitric oxide metabolites and increased plasma levels of asymmetric dimethylarginine in men with essential hypertension. J Cardiovasc Pharmacol. 1999;33:652–658.
    OpenUrlCrossRefPubMed
  49. ↵
    Boger RH, Bode-Boger SM, Szuba A, Tsao PS, Chan JR, Tangphao O, Blaschke TF, Cooke JP. Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation. 1998;98:1842–1847.
    OpenUrlAbstract/FREE Full Text
  50. ↵
    Yu XJ, Li YJ, Xiong Y. Increase of an endogenous inhibitor of nitric oxide synthesis in serum of high cholesterol fed rabbits. Life Sci. 1994;54:753–758.
    OpenUrlCrossRefPubMed
  51. ↵
    Bode-Boger SM, Boger RH, Kienke S, Junker W, Frolich JC. Elevated l-arginine/dimethylarginine ratio contributes to enhanced systemic NO production by dietary l-arginine in hypercholesterolemic rabbits. Biochem Biophys Res Commun. 1996;219:598–603.
    OpenUrlCrossRefPubMed
  52. ↵
    Matsuoka H, Itoh S, Kimoto M, Kohno K, Tamai O, Wada Y, Yasukawa H, Iwami G, Okuda S, Imaizumi T. Asymmetrical dimethylarginine, an endogenous nitric oxide synthase inhibitor, in experimental hypertension. Hypertension. 1997;29(pt 2):242–247.
  53. ↵
    Fard A, Tuck C, Donis J, Sciacca R, DiTullio M, Wu H, Bryant T, Chen N, Torres-Tamayo M, Ramasamy R, Berglund L, Ginsberg H, Homma S, Cannon P. Acute elevations of plasma asymmetric dimethylarginine and impaired endothelial function in response to a high-fat meal in patients with type 2 diabetes. Arterioscler Thromb Vasc Biol. In press.
  54. Ogawa T, Kimoto M, Sasaoka K. Dimethylarginine:pyruvate aminotransferase in rats: purification, properties, and identity with alanine:glyoxylate aminotransferase. J Biol Chem. 1990;265:20938–20945.
    OpenUrlAbstract/FREE Full Text
  55. ↵
    Najbauer J, Johnson BA, Young AL, Aswad DW. Peptides with sequences similar to glycine, arginine-rich motifs in proteins interacting with RNA are efficiently recognized by methyltransferase(s) modifying arginine in numerous proteins. J Biol Chem. 1993;268:10501–10509.
    OpenUrlAbstract/FREE Full Text
  56. ↵
    Ghosh SK, Paik WK, Kim S. Purification and molecular identification of two protein methylases I from calf brain: myelin basic protein- and histone-specific enzyme. J Biol Chem. 1988;263:19024–19033.
    OpenUrlAbstract/FREE Full Text
  57. ↵
    Tang J, Frankel A, Cook RJ, Kim S, Paik WK, Williams KR, Clarke S, Herschman HR. PRMT1 is the predominant type I protein arginine methyltransferase in mammalian cells. J Biol Chem. 2000;275:7723–7730.
    OpenUrlAbstract/FREE Full Text
  58. ↵
    Ogawa T, Kimoto M, Sasaoka K. Occurrence of a new enzyme catalyzing the direct conversion of NG,NG-dimethyl-l-arginine to l-citrulline in rats. Biochem Biophys Res Commun. 1987;148:671–677.
    OpenUrlCrossRefPubMed
  59. ↵
    Leiper JM, Santa Maria J, Chubb A, MacAllister RJ, Charles IG, Whitley GS, Vallance P. Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and homology with microbial arginine deiminases. Biochem J. 1999;343(pt 1):209–214.
  60. ↵
    McDermott. Studies on the catabolism of NG-methylarginine, NG,N′G-dimethylarginine and NG,NG-dimethylarginine in the rabbit. Biochem J. 1976;154:179–184.
    OpenUrlAbstract/FREE Full Text
  61. ↵
    MacAllister RJ, Rambausek MH, Vallance P, Williams D, Hoffman KH, Ritz E. Concentration of dimethyl-l-arginine in the plasma of patients with end-stage renal failure. Nephrol Dial Transplant. 1996;11:2449–2452.
    OpenUrlAbstract/FREE Full Text
  62. ↵
    MacAllister RJ, Parry H, Kimoto M, Ogawa T, Russell RJ, Hodson H, Whitley GS, Vallance P. Regulation of nitric oxide synthesis by dimethylarginine dimethylaminohydrolase. Br J Pharmacol. 1996;119:1533–1540.
    OpenUrlCrossRefPubMed
  63. ↵
    Ito A, Tsao PS, Adimoolam S, Kimoto M, Ogawa T, Cooke JP. Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase. Circulation. 1999;99:3092–3095.
    OpenUrlAbstract/FREE Full Text
  64. ↵
    Pollock JS, Forstermann U, Mitchell JA, Warner TD, Schmidt HH, Nakane M, Murad F. Purification and characterization of particulate endothelium-derived relaxing factor synthase from cultured and native bovine aortic endothelial cells. Proc Natl Acad Sci U S A. 1991;88:10480–10484.
    OpenUrlAbstract/FREE Full Text
  65. ↵
    Cooke JP, Andon NA, Girerd XJ, Hirsch AT, Creager MA. Arginine restores cholinergic relaxation of hypercholesterolemic rabbit thoracic aorta. Circulation. 1991;83:1057–1062.
    OpenUrlAbstract/FREE Full Text
  66. ↵
    Drexler H, Zeiher AM, Meinzer K, Just H. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by l-arginine. Lancet. 1991;338:1546–1550.
    OpenUrlCrossRefPubMed
  67. ↵
    Clarkson P, Adams MR. Powe AJ, Donald AE, McCredie R, Robinson J, McCarthy SN, Keech A, Celermajer DS, Deanfield JE. Oral l-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults. J Clin Invest.. 1996;97:1989–1994.
    OpenUrlPubMed
  68. ↵
    Ceremuzynski L, Chamiec T, Herbaczynska-Cedro K. Effect of supplemental oral l-arginine on exercise capacity in patients with stable angina pectoris. Am J Cardiol. 1997;80:331–333.
    OpenUrlCrossRefPubMed
  69. ↵
    Boger RH, Bode-Boger SM, Thiele W, Creutzig A, Alexander K, Frolich JC. Restoring vascular nitric oxide formation by l-arginine improves the symptoms of intermittent claudication in patients with peripheral arterial occlusive disease. J Am Coll Cardiol. 1998;32:1336–1344.
    OpenUrlCrossRefPubMed
  70. ↵
    Lerman A, Burnett JC Jr, Higano ST, McKinley LJ, Holmes DR Jr. Long-term l-arginine supplementation improves small-vessel coronary endothelial function in humans. Circulation. 1998;97:2123–2128.
    OpenUrlAbstract/FREE Full Text
  71. ↵
    Maxwell A, Anderson B, Cooke JP. Nutritional therapy for peripheral arterial disease: a double blind, placebo-controlled randomized trial of HeartBar. Vasc Med.. 2000;5:11–19.
    OpenUrlAbstract/FREE Full Text
  72. ↵
    McDonald KK, Zharikov S, Block ER, Kilberg MS. A caveolar complex between the cationic amino acid transporter 1 and endothelial nitric-oxide synthase may explain the ‘arginine paradox.’ J Biol Chem. 1997;272:31213–31216.
    OpenUrlAbstract/FREE Full Text
  73. ↵
    Faraci FM, Brian JE Jr, Heistad DD. Response of cerebral blood vessels to an endogenous inhibitor of nitric oxide synthase. Am J Physiol. 1995;269(pt 2):H1522–H1527.
  74. ↵
    Chan J, Böger R, Bode-Böger S, Tangphao O, Tsao P, Blaschke T, Cooke J. Asymmetric dimethylarginine increases mononuclear cell adhesiveness in hypercholesterolemic humans. Arterioscler Thromb Vasc Biol. 2000;20:1040–1046.
    OpenUrlAbstract/FREE Full Text
  75. ↵
    Theilmeier G, Chan J, Zalpour C, Ma A, Anderson B, Wang B-Y, Wolf A, McEvoy L, Butcher E, Tsao PS, Cooke JP. Adhesiveness of mononuclear cells in hypercholesterolemic humans is normalized by dietary arginine. Arterioscler Thromb Vasc Biol.. 1997;17:3557–3564.
    OpenUrlAbstract/FREE Full Text
  76. ↵
    Adams MR, McCredie R, Jessup W, Robinson J, Sullivan D, Celermajer DS. Oral l-arginine improves endothelium-dependent dilatation and reduces monocyte adhesion to endothelial cells in young men with coronary artery disease. Atherosclerosis. 1997;129:261–269.
    OpenUrlCrossRefPubMed
  77. ↵
    Huang PL. Disruption of the endothelial nitric oxide synthase gene: effect on vascular response to injury. Am J Cardiol. 1998;82(10A):57S–59S.
  78. ↵
    Cooke JP, Singer AH, Tsao PS, Zera P, Rowan RA, Billingham ME. Anti-atherogenic effects of l-arginine in the hypercholesterolemic rabbit. J Clin Invest. 1992;90:1168–1172.
  79. ↵
    McNamara DB, Bedi B, Aurora H, Tena L, Ignarro LJ, Kadowitz PJ, Akers DL. l-Arginine inhibits balloon catheter-induced intimal hyperplasia. Biochem Biophys Res Commun.. 1993;193:291–296.
    OpenUrlCrossRefPubMed
  80. ↵
    Tarry WC, Makhoul RG. l-Arginine improves endothelium-dependent vasorelaxation and reduces intimal hyperplasia after balloon angioplasty. Arterioscler Thromb. 1994;14:938–943.
    OpenUrlAbstract/FREE Full Text
  81. ↵
    Hamon M, Vallet B, Bauters C, Wernert N, McFadden EP, Lablanche JM, Dupuis B, Bertrand ME. Long-term oral administration of l-arginine reduces intimal thickening and enhances neoendothelium-dependent acetylcholine-induced relaxation after arterial injury. Circulation. 1994;90:1357–1362.
    OpenUrlAbstract/FREE Full Text
  82. ↵
    Wang BY, Candipan RC, Arjomandi M, Hsiun PT, Tsao PS, Cooke JP. Arginine restores nitric oxide activity and inhibits monocyte accumulation after vascular injury in hypercholesterolemic rabbits. J Am Coll Cardiol. 1996;28:1573–1579.
    OpenUrlCrossRefPubMed
  83. ↵
    Candipan RC, Wang B, Buitrago R, Tsao PS, Cooke JP. Regression or progression: dependency on vascular nitric oxide. Arterioscler Thromb Vasc Biol. 1996;16:44–50.
    OpenUrlAbstract/FREE Full Text
  84. ↵
    Aji W, Ravalli S, Szabolcs M, Jiang XC, Sciacca RR, Michler RE, Cannon PJ. l-Arginine prevents xanthoma development and inhibits atherosclerosis in LDL receptor knockout mice. Circulation. 1997;95:430–437.
    OpenUrlAbstract/FREE Full Text
  85. ↵
    Boger RH, Bode-Boger SM, Brandes RP, Phivthong-ngam L, Bohme M, Nafe R, Mugge A, Frolich JC. Dietary l-arginine reduces the progression of atherosclerosis in cholesterol-fed rabbits: comparison with lovastatin. Circulation. 1997;96:1282–1290.
    OpenUrlAbstract/FREE Full Text
  86. ↵
    Schwarzacher SP, Lim TT, Wang B, Kernoff RS, Niebauer J, Cooke JP, Yeung AC. Local intramural delivery of l-arginine enhances nitric oxide generation and inhibits lesion formation after balloon angioplasty. Circulation. 1997;95:1863–1869.
    OpenUrlAbstract/FREE Full Text
  87. ↵
    Weidinger FF, McLenachan JM, Cybulsky M, Gordon JM, Rennke HA, Hollenberg NK, Ganz P, Cooke JP. Persistent dysfunction of regenerated endothelium following balloon angioplasty of rabbit iliac artery. Circulation. 1990;81:1667–1679.
  88. ↵
    Azuma H, Sato J, Hamasaki H, Sugimoto A, Isotani E, Obayashi S. Accumulation of endogenous inhibitors for nitric oxide synthesis and decreased content of l-arginine in regenerated endothelial cells. Br J Pharmacol. 1995;115:1001–1004.
    OpenUrlPubMed
  89. ↵
    Masuda H, Goto M, Tamaoki S, Azuma H. Accelerated intimal hyperplasia and increased endogenous inhibitors for NO synthesis in rabbits with alloxan-induced hyperglycaemia. Br J Pharmacol. 1999;126:211–218.
    OpenUrlCrossRefPubMed
  90. ↵
    Miyazaki H, Matsuoka H, Cooke JP, Usui M, Ueda S, Okuda S, Imaizumi T. Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis. Circulation. 1999;99:1141–1146.
    OpenUrlAbstract/FREE Full Text
  91. ↵
    Murakami T, Mizuno S, Kaku B. Clinical morbidities in subjects with Doppler-evaluated endothelial dysfunction of coronary artery. J Am Coll Cardiol. 1998;31(suppl A):419A. Abstract.
  92. ↵
    Schächinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation.. 2000;101:1899–1906.
    OpenUrlAbstract/FREE Full Text
View Abstract

This Issue

Jump to

Article Tools

Share this Article

  • Email
  • Does ADMA Cause Endothelial Dysfunction?
    John P. Cooke
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:2032-2037, originally published September 1, 2000
    https://doi.org/10.1161/01.ATV.20.9.2032
    Permalink:
    del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo

Related Articles

Cited By...

Subjects