Asymmetric Dimethylarginine (ADMA) and other Endogenous Nitric Oxide Synthase (NOS) Inhibitors as an Important Cause of Vascular Insulin Resistance

Abstract

Asymmetric dimethylarginine (ADMA) and NG-monomethyl-L-arginine (L-NMMA) are important endogenous endothelial nitric oxide synthase (eNOS) inhibitors. Studies have shown that patients with insulin resistance have elevated plasma levels of ADMA. Moreover, ADMA levels have a prognostic value on long-term outcome of patients with coronary artery disease. Insulin resistance, a disorder associated to inadequate biological responsiveness to the actions of exogenous or endogenous insulin, is a metabolic condition, which exists in patients with cardiovascular diseases. This disorder affects the functional balance of vascular endothelium via changes of nitric oxide (NO) metabolism. Nitric oxide is produced in endothelial cells from the substrate L-arginine via eNOS. Elevated ADMA levels cause eNOS uncoupling, a mechanism which leads to decreased NO bioavailability and increased production of hydrogen peroxide. According to clinical studies, the administration of L-arginine to patients with high ADMA levels improves NO synthesis by antagonizing the deleterious effect of ADMA on eNOS function, although in specific populations such as diabetes mellitus, this might even been harmful. More studies are required in order to certify the role of NOS inhibitors in insulin resistance and endothelial dysfunction. It is still difficult to say whether increased ADMA levels in certain populations is only a reason or the result of the molecular alterations, which take place in vascular disease states.

endothelium - NOS inhibitors - insulin resistance

References

• 1 Boger RH. Asymmetric dimethylarginine (ADMA): a novel risk marker in cardiovascular medicine and beyond.  Ann Med. 2006;  38 126-136
• 2 Boger RH. Asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, explains the “L-arginine paradox” and acts as a novel cardiovascular risk factor.  J Nutr. 2004;  134 ((Suppl 10)) 2842S-2847S , discussion 2853S
• 3 Tousoulis D, Antoniades C, Stefanadis C. Statins ameliorate atherosclerosis induced by inhibition of nitric oxide synthase: another novel vascular protective mechanism?.  Int J Cardiol. 2008;  123 91-93
• 4 Kim JA, Montagnani M, Koh KK, Quon MJ. Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms.  Circulation. 2006;  113 1888-1904
• 5 Park YW, Zhu S, Palaniappan L, Heshka S, Carnethon MR, Heymsfield SB. The metabolic syndrome: prevalence and associated risk factor findings in the US population from the third national health and nutrition examination survey, 1988–1994.  Arch Intern Med. 2003;  163 427-436
• 6 Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third national health and nutrition examination survey.  JAMA. 2002;  287 356-359
• 7 Apridonidze T, Essah PA, Iuorno MJ, Nestler JE. Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome.  J Clin Endocrinol Metab. 2005;  90 1929-1935
• 8 Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith Jr SC, Spertus JA, Costa F. American Heart Association; National Heart, Lung, and Blood Institute . Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement.  Circulation. 2005;  112 2735-2752
• 9 Lorenzo C, Williams K, Hunt KJ, Haffner SM. The National Cholesterol Education Program – Adult Treatment Panel III, international diabetes federation, and World Health Organization definitions of the metabolic syndrome as predictors of incident cardiovascular disease and diabetes.  Diabetes Care. 2007;  30 8-13
• 10 Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) . Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III).  JAMA. 2001;  285 2486-2497
• 11 Alberti KG, Zimmet P, Shaw J. The metabolic syndrome – a new worldwide definition.  Lancet. 2005;  366 ((9491)) 1059-1062
• 12 Genuth S, Alberti KG, Bennett P, Buse J, Defronzo R, Kahn R, Kitzmiller J, Knowler WC, Lebovitz H, Lernmark A, Nathan D, Palmer J, Rizza R, Saudek C, Shaw J, Steffes M, Stern M, Tuomilehto J, Zimmet P. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus . Follow-up report on the diagnosis of diabetes mellitus.  Diabetes Care. 2003;  26 3160-3167
• 13 Third Report of the National Cholesterol Education Program (NCEP) . Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.  Circulation. 2002;  106 3143-3421
• 14 Hanley AJ, Karter AJ, Williams K, Festa A, D’Agostino Jr RB, Wagenknecht LE, Haffner SM. Prediction of type 2 diabetes mellitus with alternative definitions of the metabolic syndrome: the insulin resistance atherosclerosis study.  Circulation. 2005;  112 3713-3721
• 15 Serrano Rios M. Relationship between obesity and the increased risk of major complications in non-insulin-dependent diabetes mellitus.  Eur J Clin Invest. 1998;  28 ((Suppl 2)) 14-17 , discussion 17–18
• 16 Scherrer U, Sartori C. Insulin as a vascular and sympathoexcitatory hormone: implications for blood pressure regulation, insulin sensitivity, and cardiovascular morbidity.  Circulation. 1997;  96 4104-4113
• 17 Reaven GM, Lithell H, Landsberg L. Hypertension and associated metabolic abnormalities – the role of insulin resistance and the sympathoadrenal system.  N Engl J Med. 1996;  334 374-381
• 18 DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance.  Am J Physiol. 1979;  237 E214-E223
• 19 Bergman RN. Lilly lecture 1989. Toward physiological understanding of glucose tolerance.  Minimal-model approach. Diabetes. 1989;  38 1512-1527
• 20 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.  Diabetologia. 1985;  28 412-419
• 21 Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, Quon MJ. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans.  J Clin Endocrinol Metab. 2000;  85 2402-2410
• 22 Hrebícek J, Janout V, Malincíková J, Horáková D, Cízek L. Detection of insulin resistance by simple quantitative insulin sensitivity check index QUICKI for epidemiological assessment and prevention.  J Clin Endocrinol Metab. 2002;  87 144-147
• 23 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 ((8793)) 572-575
• 24 Cooke JP. Does ADMA cause endothelial dysfunction?.  Arterioscler Thromb Vasc Biol. 2000;  20 2032-2037
• 25 Agote Robertson M, Finochietto P, Gamba CA, Dagrosa MA, Viaggi ME, Franco MC, Poderoso JJ, Juvenal GJ, Pisarev MA. Nicotinamide increases thyroid radiosensitivity by stimulating nitric oxide synthase expression and the generation of organic peroxides.  Horm Metab Res. 2006;  38 12-15
• 26 Cooke JP, Dzau VJ. Nitric oxide synthase: role in the genesis of vascular disease.  Annu Rev Med. 1997;  48 489-509
• 27 Tentolouris C, Tousoulis D, Goumas G, Stefanadis C, Davies G, Toutouzas P. L-Arginine in coronary atherosclerosis.  Int J Cardiol. 2000;  75 123-128
• 28 Tousoulis D, Antoniades C, Tentolouris C, Goumas G, Stefanadis C, Toutouzas P. L-arginine in cardiovascular disease: dream or reality?.  Vasc Med. 2002;  7 203-211
• 29 Celermajer DS, Sorensen KE, Georgakopoulos D, Bull C, Thomas O, Robinson J, Deanfield JE. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults.  Circulation. 1993;  88 2149-2155
• 30 Johnstone MT, Creager SJ, Scales KM, Cusco JA, Lee BK, Creager MA. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus.  Circulation. 1993;  88 2510-2516
• 31 Hingorani AD, Cross J, Kharbanda RK, Mullen MJ, Bhagat K, Taylor M, Donald AE, Palacios M, Griffin GE, Deanfield JE, MacAllister RJ, Vallance P. Acute systemic inflammation impairs endothelium-dependent dilatation in humans.  Circulation. 2000;  102 994-999
• 32 Heitzer T, Krohn K, Albers S, Meinertz T. Tetrahydrobiopterin improves endothelium-dependent vasodilation by increasing nitric oxide activity in patients with Type II diabetes mellitus.  Diabetologia. 2000;  43 1435-1438
• 33 Fontana J, Fulton D, Chen Y, Fairchild TA, MacCabe TJ, Fujita N, Tsuruo T, Sessa WC. Domain mapping studies reveal that the M domain of hsp90 serves as a molecular scaffold to regulate Akt-dependent phosphorylation of endothelial nitric oxide synthase and NO release.  Circ Res. 2002;  90 866-873
• 34 Pritchard Jr KA, Ackerman AW, Gross ER, Stepp DW, Shi Y, Fontana JT, Baker JE, Sessa WC. Heat shock protein 90 mediates the balance of nitric oxide and superoxide anion from endothelial nitric-oxide synthase.  J Biol Chem. 2001;  276 17621-17624
• 35 Schneider R, Raff U, Vornberger N, Schmidt M, Freund R, Reber M, Schramm L, Gambaryan S, Wanner C, Schmidt HH, Galle J. L-Arginine counteracts nitric oxide deficiency and improves the recovery phase of ischemic acute renal failure in rats.  Kidney Int. 2003;  64 216-225
• 36 MacNeill AM, Rosamond WD, Girman CJ, Golden SH, Schmidt MI, East HE, Ballantyne CM, Heiss G. The metabolic syndrome and 11-year risk of incident cardiovascular disease in the atherosclerosis risk in communities study.  Diabetes Care. 2005;  28 385-390
• 37 Landmesser U, Dikalov S, Price SR, MacCann L, Fukai T, Holland SM, Mitch WE, Harrison DG. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension.  J Clin Invest. 2003;  111 1201-1209
• 38 Weisberg SP, MacCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante Jr AW. Obesity is associated with macrophage accumulation in adipose tissue.  J Clin Invest. 2003;  112 1796-1808
• 39 Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2 diabetes.  Science. 2005;  307 ((5708)) 384-387
• 40 Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes.  N Engl J Med. 2004;  350 664-671
• 41 Schnabel R, Blankenberg S, Lubos E, Lackner KJ, Rupprecht HJ, Espinola-Klein C, Jachmann N, Post F, Peetz D, Bickel C, Cambien F, Tiret L, Münzel T. Asymmetric dimethylarginine and the risk of cardiovascular events and death in patients with coronary artery disease: results from the AtheroGene Study.  Circ Res. 2005;  97 e53-e59
• 42 Cardillo C, Nambi SS, Kilcoyne CM, Choucair WK, Katz A, Quon MJ, Panza JA. Insulin stimulates both endothelin and nitric oxide activity in the human forearm.  Circulation. 1999;  100 820-825
• 43 Cardillo C, Campia U, Bryant MB, Panza JA. Increased activity of endogenous endothelin in patients with type II diabetes mellitus.  Circulation. 2002;  106 1783-1787
• 44 Jiang DJ, Jia SJ, Dai Z, Li YJ. Asymmetric dimethylarginine induces apoptosis via p38 MAPK/caspase-3-dependent signaling pathway in endothelial cells.  J Mol Cell Cardiol. 2006;  40 529-539
• 45 Andreotti F, Becker RC. Atherothrombotic disorders: new insights from hematology.  Circulation. 2005;  111 1855-1863
• 46 Kissel CK, Lehmann R, Assmus B, Aicher A, Honold J, Fischer-Rasokat U, Heeschen C, Spyridopoulos I, Dimmeler S, Zeiher AM. Selective functional exhaustion of hematopoietic progenitor cells in the bone marrow of patients with postinfarction heart failure.  J Am Coll Cardiol. 2007;  49 2341-2349
• 47 Clarke S. Protein methylation.  Curr Opin Cell Biol. 1993;  5 977-983
• 48 MacBride AE, Silver PA. State of the arg: protein methylation at arginine comes of age.  Cell. 2001;  106 5-8
• 49 Vallance P, Leiper J. Cardiovascular biology of the asymmetric dimethylarginine:dimethylarginine dimethylaminohydrolase pathway.  Arterioscler Thromb Vasc Biol. 2004;  24 1023-1030
• 50 Vallance P, Leone A, Calver A, Collier J, Moncada S. Endogenous dimethylarginine as an inhibitor of nitric oxide synthesis.  J Cardiovasc Pharmacol. 1992;  20 ((Suppl 12)) S60-S62
• 51 Kimoto M, Whitley GS, Tsuji H, Ogawa T. Detection of NG, NG-dimethylarginine dimethylaminohydrolase in human tissues using a monoclonal antibody.  J Biochem (Tokyo). 1995;  117 237-238
• 52 Boger RH. The emerging role of asymmetric dimethylarginine as a novel cardiovascular risk factor.  Cardiovasc Res. 2003;  59 824-833
• 53 Coluzzi G, Santucci E, Marzo F, Andreotti F. Asymmetric dimethylarginine and impaired cardiovascular healing.  J Thromb Thrombolysis. 2007 Dec 10;  , [Epub ahead of print]
• 54 Garcia RG, Perez M, Maas R, Schwedhelm E, Böger RH, López-Jaramillo P. Plasma concentrations of asymmetric dimethylarginine (ADMA) in metabolic syndrome.  Int J Cardiol. 2007;  122 176-178
• 55 Faraci FM, Brian Jr JE, Heistad DD. Response of cerebral blood vessels to an endogenous inhibitor of nitric oxide synthase.  Am J Physiol. 1995;  269 ((5 Pt 2)) H1522-H1527
• 56 MacLaughlin T, Stühlinger M, Lamendola C, Abbasi F, Bialek J, Reaven GM, Tsao PS. Plasma asymmetric dimethylarginine concentrations are elevated in obese insulin-resistant women and fall with weight loss.  J Clin Endocrinol Metab. 2006;  91 1896-1900
• 57 Heutling D, Schulz H, Nickel I, Kleinstein J, Kaltwasser P, Westphal S, Mittermayer F, Wolzt M, Krzyzanowska K, Randeva H, Schernthaner G, Lehnert H. Asymmetrical dimethylarginine, inflammatory and metabolic parameters in women with polycystic ovary syndrome before and after metformin treatment.  J Clin Endocrinol Metab. 2008;  93 82-90
• 58 Pistrosch F, Passauer J, Fischer S, Fuecker K, Hanefeld M, Gross P. In type 2 diabetes, rosiglitazone therapy for insulin resistance ameliorates endothelial dysfunction independent of glucose control.  Diabetes Care. 2004;  27 484-490
• 59 Jacobi J, Sydow K, Degenfeld G von, Zhang Y, Dayoub H, Wang B, Patterson AJ, Kimoto M, Blau HM, Cooke JP. Overexpression of dimethylarginine dimethylaminohydrolase reduces tissue asymmetric dimethylarginine levels and enhances angiogenesis.  Circulation. 2005;  111 1431-1438
• 60 Knipp M, Braun O, Vasak M. Searching for DDAH inhibitors: S-Nitroso-L-homocysteine is a chemical lead.  J Am Chem Soc. 2005;  127 2372-2373
• 61 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
• 62 Konishi H, Sydow K, Cooke JP. Dimethylarginine dimethylaminohydrolase promotes endothelial repair after vascular injury.  J Am Coll Cardiol. 2007;  49 1099-1105
• 63 Stühlinger MC, Abbasi F, Chu JW, Lamendola C, MacLaughlin TL, Cooke JP, Reaven GM, Tsao PS. Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor.  JAMA. 2002;  287 1420-1406
• 64 Tousoulis D, Xenakis C, Tentolouris C, Davies G, Antoniades C, Crake T, Stefanadis C. Effects of vitamin C on intracoronary L-arginine dependent coronary vasodilatation in patients with stable angina.  Heart. 2005;  91 1319-1323
• 65 Lerman A, Burnett Jr JC, Higano ST, MacKinley LJ, Holmes Jr DR. Long-term L-arginine supplementation improves small-vessel coronary endothelial function in humans.  Circulation. 1998;  97 2123-2128
• 66 Schulman SP. L-arginine therapy in acute myocardial infarction: the vascular interaction with age in myocardial infarction (VINTAGE MI) randomized clinical trial.  JAMA. 2006;  295 58-64
• 67 Channon KM, Guzik TJ. Mechanisms of superoxide production in human blood vessels: relationship to endothelial dysfunction, clinical and genetic risk factors.  J Physiol Pharmacol. 2002;  53 515-524

Correspondence