ADMA

(Asymmetric dimethylarginine)

NO
Laboratoire Philippe Auguste 119 Avenue Philippe Auguste 75011 Paris France Tel: 0143675700 Fax : 0143790027 Email: contact@labbio.net

Annexe
ADMA or Asymmetric dimethylarginine Origin of ADMA.....1 ADMA Catabolism.... 2 DDAH .3 NO Vascular protector ..4 ADMA physiology and et pathology......5 ADMA Factor and Index of Vascular Aging index and factor ..6 Treatment7 References...7

ADMA (Asymmetric dimethylarginine)

A cardio-vascular risk factor and a marker of vascular aging

Origin of ADMA
ADMA originates from the turn-over of methylated proteins involved in nuclear physiology, transcription, DNA and protein binding. These proteins are methylated on the guanidine group of arginine by specific enzymes, PRMT (Protein Arginine Methyl Transferases), which exist in 2 isoforms: PRMT-1 which transfers 2 methyls on the same N of the guanidine group, giving ADMA (Asymmetrical Dimethyl Arginine), and PRMT-2 which methylates symmetrically the 2 N of the guanidine providing SDMA (Symmetrical Dimethyl Arginine)1 fig.1.

Fig. 1 The synthesis of methylated forms of Arginine

PRMTs and NOs tissue distribution are superposable. ADMA is endogenous inhibitor of all NOs of which exist 3 isoforms: eNOs in endothelium, nNOs in CNS and iNOs for inducible enymatic form by inflammation especially. The 2 other arginine methylated derivatives are MMA (Mono Methyl Arginine), synthesized by both PRMTs, which is also a potent inhibitor of NOs and SDMA without inhibitory effect, but competitor on the active amino acid Y+ transport system.(fig.2).

Fig. 2 Methylated derivatives of Arginine

Laboratoire Philippe Auguste

ADMA catabolism
320 moles of ADMA are released each day by the turn-over of methylated proteins. 80% (260 moles/50mg) are degraded into citrullin and dimethylamine by DDAH (Dimethyl Di Amino Hydrolase), of which exist 2 isoforms 1 & 2 associated respectively to nNOs & eNOs2.

Protein
SAM SAH PRMT I

Protein with ADMA O2

Hydrolysis

ADMA

Dimethylamine + Citrulline

Renal Excretion

Fig. 3 Metabolism of PRMT-ADMA-DDAH

SDMA is excreted without modification by the kidney

80 %

20 %

100 %

Fig. 4 SDMA eliminates without modification, ADMA degradation by DDAH

Laboratoire Philippe Auguste

Crucial role of DDAH

DDAH, which polymorphism has been recently discovered, indirectly activates NOs by clearing its endogenous inhibitor, ADMA But DDAH is regulated by negative feed- back3and is inactivated or depressed in 2 physiological conditions: -In oxidative stress, ROS oxidize definitely thiol cystein active site(fig 6). -In inflammation, iNOs overproducced NO nitrosyle the same cysteine in a reversible manner4 (fig 5), .

Fig. 5 Metabolism of methylated arginine can be directly regulated by NO

Fig. 6 Oxidative stredd inhibits the activity of DDAH

Inversely, DDAH surexpression in transgenic mice leads to increased NO production and clinical expression of associated properties as vascular protection and angiogenesis.
Laboratoire Philippe Auguste

NO Vascular protector
Inhibits endothekium adhesivity and penetration By circulating monocytes Mediates vasodilation (EDRF)

NO
Reduces platelet adhesiveness Inhibits media smooth muscle cells proliferation, key step in atherogenesis

Fig. 7 How NOmediates vasomotion and protects vessel wall

Vascular NO reduction enhances atherogenesis: NO is a potent vascular protector Inducex Inducex Endothlial Endothlial Dysfunction Dysfunction Increases Increases monocyte monocyte chemoattractive chemoattractive Protein Protein (MCP-1) (MCP-1) release release

Increases Increases vascular vascular rsistance rsistance

Promotes Promotes media media Smooth muscle Smooth muscle cells cells proliferation proliferation

NO

Increases Increases arterial arterial pressure pressure

induces induces vasospasmi vasospasmi Increases Increases endothelial-cell endothelial-cell adhesiveness adhesiveness

Enhances Enhances platelet platelet adhesiveness adhesiveness

Fig. 8 Molecular Mcanisms and cellular molecular caused by the diminution of NO production Laboratoire Philippe Auguste

ADMA in physiology and pathology

ADMA inhibits NOs and produces the effects expected of an non isoform specific NOs atagonist. It elevates blood pressure, vascular resistance, reduces vessel vasodilation and increases endothelium cell adhesiveness. In the heart, ADMA reduces heart rate, cardiac output and systolic ejection fraction. In the kidney, ADMA reduces perfusion, sodium excretion and causes reno-vascular hypertension. Long term exposure to ADMA would cause atherogenesis, hypertension with damage to end organs as renal and heart failure5,6. Increased plasma ADMA has been reported in a wide range of cardio-vascular disease.Its early elevation designs it as a pathogenic factor ad a predicitive marker in : Cardio vascular rik factors7,8 In which ADMA, early increased in young subjects, is the marker of endothelial dysfunction in hypercholesterolemia9, hypertension10, type 2 diabetes11, insulin resistance, hyperhomocysteinemia, smoking9,12,13.
Diminution de Diminution Diminutionof de production de production de NO NO NO production

+ + --

Augmentation de Augmentation de of Augmentation lADMA lADMA ADMA

+ +

smoking Tabagisme

Tabagisme

endothelial DYSFONCTION DYSFONCTION ENDOTHELIALE ENDOTHELIALE dysfunction

Insulino Insulin Insulino r resistance r sistance sistance

Ob Obesity Ob sit sit Hypercholest hypercholesterolemia Hypercholest rol rol mie mie

Diabete Diab Diab te te

Hyperhomocyst Hyperhomocyst in in mie mie hyperhomocysteinemia

Hypertension Hypertension

sedentarity S S dentarit dentarit

Fig. 9 Risk factors that make endothelial dysfunction with augmentation of ADMA and diminution of NO production

Atherosclerosis and cardiovascular diseases Erectile Dysfunction15,16,17

Laboratoire Philippe Auguste

Renal failure18,19 Plasma ADMA level is predictive of mortality, SDMA being exclusively excreted by the kidney, ADMA/SDMA ratio is modified. Heart Failure20,21 ADMA reduces ventricular contraction and systolic eljection fraction by a direct cardiac effect ? Pulmonary Hypertension 22,23 ADMA levels are raised in children with pulmonary hypertension. In experimental animal models of hypoxia inuced pulmonary hypertension, ADMA accumulation is linked to DDAH down-regulation? Preeclampsy24,25 ADMA elevation before the develoment of preeclampsy suggest that it would provide a risk marker in this disease. Fast growing foetus produces large amounts of ADMA which is detoxified by high level expressed placenta DDAH.

ADMA is a factor and a marker of vascular aging

Many studies have shown that atherosclerosis was initiated by prior endothelium alteration described as endothelial dysfuction 26,27. Depletion of NO, fountain of youth of the vessel wall, depresses angiogenenesis and mediates all main atherogenesis molecular and cellular mechanisms from enddothelium to media28,29.

Fig. 10 Uncouping of NO synthase by ADMA and O2-

In vitro, ADMA accelerates endothelial cell senescence probably by two mechanisms : inhibition of NOs activity and oxidative stress inducing telomeres shorteniong and reduced telomerase activity.*30,31.
Laboratoire Philippe Auguste

Treatment
ADMA = vascular NO 3 therapeutic Strategies Rduction ADMA-NOs inhibition

ADMA levels reduction

NO synthase stimulation Reduces O2& ADMA NOs uncoupling Release NOs by reducing caveolin

32,33 L-ARGININE L-ARGININE32,33

34 Retinoic Retinoic Acid Acid34 Thiazolidinediones Thiazolidinediones 35 Estrogens Estrogens35 Metformine Metformine

Tetrahydrobiopterin Tetrahydrobiopterin (BH4) (BH4)

Statins Statins

References
1. 2. 3. 4. McBride AE, Silver PA. State of the Arg: protein methylation at arginine comes of age. Cell. 2001; 106: 58. Tran Cam TL, Fox MF, Vallance P, Leiper J. Chromosomal localization, gene structure and expression pattern of DDAH1: comparison with DDAH2 and implications for evolutionary origins. Genomics. 2000; 68: 101105. Jones LC, Tran CT, Leiper JM, Hingorani AD, Vallance P. Common genetic variation in a basal promoter element alters DDAH2 expression in endothelial cells. Biochem Biophys Res Commun. 2003; 310: 836843. Leiper J, Murray-Rust J, McDonald N, Vallance P. S-nitrosylation of dimethylarginine dimethylaminohydrolase regulates enzyme activity: further interactions between nitric oxide synthase and dimethylarginine dimethylaminohydrolase. Proc Natl Acad Sci U S A. 2002; 99: 1352713532. Boger RH, Bode-Boger SM, Tsao PS, Lin PS, Chan JR, Cooke JP. An endogenous inhibitor of nitric oxide synthase regulates endothelial adhesiveness for monocytes. J Am Coll Cardiol. 2000; 36: 22872295. 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: 753759. John P. Cooke Does ADMA Cause Endothelial Dysfunction? Arterioscler. Thromb. Vasc. Biol., 2000; 20: 2032 2037. Vallance P. , Leiper J. Cardiovascular Biology of the Asymmetric Dimethylarginine:Dimethylarginine Dimethylaminohydrolase Pathway Arterioscler. Thromb. Vasc. Biol., 2004; 24. Boger RH, Bode-Boger SM, Sydow K, Heistad DD, Lentz SR. Plasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, is elevated in monkeys with hyperhomocyst(e)inemia or hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2000; 20: 15571564. Goonasekera CD, Rees DD, Woolard P, Frend A, Shah V, Dillon MJ. Nitric oxide synthase inhibitors and hypertension in children and adolescents. J Hypertens. 1997; 15: 901909. Xiong Y, Fu YF, Fu SH, Zhou HH. Elevated levels of the serum endogenous inhibitor of nitric oxide synthase and metabolic control in rats with streptozotocin-induced diabetes. J Cardiovasc Pharmacol. 2003; 42: 191 196. Stuhlinger MC, Tsao PS, Her JH, Kimoto M, Balint RF, Cooke JP. Homocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine. Circulation. 2001; 104: 25692575. Boger RH, Lentz SR, Bode-Boger SM, Knapp HR, Haynes WG. Elevation of asymmetrical dimethylarginine may mediate endothelial dysfunction during experimental hyperhomocyst(e) inaemia in humans. Clin Sci. 2001; 100: 161 167 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: 11411146

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Laboratoire Philippe Auguste

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Elesber AA, Solomon H, Lennon RJ Coronary endothelial dysfunction is associated with erectile dysfunction and elevated asymmetric dimethylarginine in patients with early atherosclerosis. Eur Heart J ;2006. Solomon H, Lennon RJ Elevation of asymmetrical dimethylarginine (ADMA) and coronary artery disease in men with erectile dysfunction. Eur Urol ; 2005 48(6):1004-11; discussion 1011-2. Mathew V, Prasad A, Pumper G, Nelson RE, McConnell JP, Asymmetric dimethyl arginine levels correlate with cardiovascular risk factors in patients with erectile dysfunction. Atherosclerosis ;2006 185(2):421-425. 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: 572576. Fermo I, Frolich J, Boger R. Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet. 2001; 358: 21132117. 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: 24252430. Saitoh M, Osanai T, Kamada T, Matsunaga T, Ishizaka H, Hanada H, Okumura K. High plasma level of asymmetric dimethylarginine in patients with acutely exacerbated congestive heart failure: role in reduction of plasma nitric oxide level. Heart Vessels. 2003; 18: 177182. Gorenflo M, Zheng C, Werle E, Fiehn W, Ulmer HE. Plasma levels of asymmetrical dimethyl-L-arginine in patients with congenital heart disease and pulmonary hypertension. J Cardiovasc Pharmacol. 2001; 37: 489492 Millatt LJ, Whitley GS, Li D, Leiper JM, Iragy HM, Carey RM, Johns RA. Evidence for dysregulation of dimethylarginine dimethylaminohydrolase I in chronic hypoxia-induced pulmonary hypertension. Circulation. 2003; 108: 14931498 Holden DP, Fickling SA, Whitley GS, Nussey SS. Plasma concentrations of asymmetric dimethylarginine, a natural inhibitor of nitric oxide synthase, in normal pregnancy and preeclampsia. Am J Obstet Gynecol. 1998; 178: 551556 Savvidou M, Hingorani A, Tsikas D, Frolich J, Vallance P, Nicolaides K. Endothelial dysfunction and raised plasma concentrations of asymmetric dimethylarginine in pregnant women who subsequently develop pre-eclampsia. Lancet. 2003; 361: 15111517 Zeiher AM, Drexler H, Saurbier B, Just H. Endothelium-mediated coronary blood flow modulation in humans: effects of age, atherosclerosis, hypercholesterolemia, and hypertension. J Clin Invest. 1993;92:652662 Celermajer DS, Sorensen KE, Spiegelhalter DJ, Georgakopoulos D, Robinson J, Deanfield JE. Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol. 1994; 24: 471476 Xu D, Neville R, Finkel T. Homocysteine accelerates endothelial cell senescence. FEBS Lett. 2000; 470: 2024. Rivard A, Fabre JE, Silver M, Chen D, Murohara T, Kearney M, Magner M, Asahara T, Isner JM. Age-dependent impairment of angiogenesis. Circulation. 1999;99:111120 Vasa M, Breitschopf K, Zeiher AM, Dimmeler S. Nitric oxide activates telomerase and delays endothelial cell senescence. Circ Res. 2000; 87: 540542 Fortunato Scalera, Jrgen Borlak, Bibiana Beckmann, Jens Martens-Lobenhoffer, Thomas Thum, Michael Tger, and Stefanie M. Bode-Bger Endogenous Nitric Oxide Synthesis Inhibitor Asymmetric Dimethyl L-Arginine Accelerates Endothelial Cell Senescence Arterioscler. Thromb. Vasc. Biol.:2004; 24: 1816 - 1822. Gregor Theilmeier, Jason R. Chan, Christoff Zalpour, Barbara Anderson, Bing-yin Wang, Andreas Wolf, Philip S. Tsao, John P. Cooke Adhesiveness of Mononuclear Cells in Hypercholesterolemic Humans Is Normalized by Dietary L-Arginine Arterioscler. Thromb. Vasc. Biol., 1997; 17: 3557 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: 13361344 Achan V, Tran CT, Arrigoni F, Leiper JM, Vallance P. All-trans-retinoic acid increases nitric oxide synthesis by endothelial cells: a role for the induction of dimethylarginine dimethylaminohydrolase. Circ Res. 2002; 90: 764769 Holden DP, Cartwright JE, Nussey SS, Whitley GS. Estrogen stimulates dimethylarginine dimethylaminohydrolase activity and the metabolism of symmetric dimethylarginine. Circulation. 2003; 108: 15751580.

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Laboratoire Philippe Auguste