ADMA_en

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Laboratoire Philippe Auguste

119 Avenue Philippe Auguste

75011 Paris France

Tel: 0143675700 Fax : 0143790027

Email: [email protected]

ADMA(Asymmetric dimethylarginine)

ADMA(Asymmetric dimethylarginine)

NONO

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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

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ADMA (Asymmetric dimethylarginine)A cardio-vascular risk factor and a marker of vascular aging

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.

Origin of ADMA

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. 1 The synthesis of methylated forms of Arginine

Fig. 2 Methylated derivatives of Arginine

Laboratoire Philippe Auguste 1

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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

Protein with ADMA

PRMT ISAM

SAH

ADMA

Hydrolysis

Dimethylamine

+ Citrulline

Renal

Excretion

O2

Fig. 3 Metabolism of PRMT-ADMA-DDAH

SDMA is excreted without modification by the kidney

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

Laboratoire Philippe Auguste 2

80 %20 %

100 %

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Fig. 6 Oxidative stredd inhibits the activity of DDAH

Crucial role of DDAH

Inversely, DDAH surexpression in transgenic mice leads to increased NO production and

clinical expression of associated properties as vascular protection and angiogenesis.

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

3Laboratoire Philippe Auguste

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), .

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Fig. 7 How NOmediates vasomotion and protects vessel wall

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


NO Vascular protector

NO

Inhibits endothekium

adhesivity and penetrationBy circulating monocytes

-

Inhibits media

smooth muscle cells

proliferation, key stepin atherogenesis

Reduces platelet

adhesiveness

Mediates vasodilation (EDRF)

- -

NONO

Inducex

Endothlial

Dysfunction

Inducex

Endothlial

Dysfunction Increases

vascular

rsistance

Increases

vascular

rsistance

Increasesarterial

pressure

Increasesarterial

pressure

induces

vasospasmi

induces

vasospasmi

Increases

endothelial-cell

adhesiveness

Increases

endothelial-cell

adhesiveness

Enhances

platelet

adhesiveness

Enhances

platelet

adhesiveness

Promotes media

Smooth muscle cells

proliferation

Promotes media

Smooth muscle cells

proliferation

Increases monocyte

chemoattractive

Protein (MCP-1) release

Increases monocyte

chemoattractive

Protein (MCP-1) release

Vascular NO reduction enhances atherogenesis:NO is a potent vascular protector

Vascular NO reduction enhances atherogenesis:NO is a potent vascular protector

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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.

DYSFONCTIONENDOTHELIALE

DYSFONCTIONENDOTHELIALE

Diminution de

production de NO

Diminution deproduction de NO

Augmentation de

lADMA

Augmentation de

lADMA

-- ++

Hypercholest rolmieHypercholest rolmie DiabteDiabte

HypertensionHypertension

S dentaritS dentarit

Insulino

rsistance

Insulino

rsistance

ObsitObsit

TabagismeTabagisme

Hyperhomocyst in mieHyperhomocyst inmie

++

Fig. 9 Risk factors that make endothelial dysfunction with augmentation of ADMA and

diminution of NO production


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 :

ADMA in physiology and pathology

Atherosclerosis and cardiovascular diseases

Erectile Dysfunction15,16,17

Insulinresistance

Obesity

Diabetehypercholesterolemia

hyperhomocysteinemia

smoking endothelialdysfunction

sedentarity

Diminution of

NO production

Augmentation of

ADMA

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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.

ADMA is a factor and a marker of vascular aging


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

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.

In vitro, ADMA accelerates endothelial cell senescence probably by two mechanisms : inhibition ofNOs activity and oxidative stress inducing telomeres shorteniong and reduced telomerase

activity.*30,31.

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1. McBride AE, Silver PA. State of the Arg: protein methylation at arginine comes of age. Cell. 2001; 106: 58.

2. Tran Cam TL, Fox MF, Vallance P, Leiper J. Chromosomal localization, gene structure and expression pattern ofDDAH1: comparison with DDAH2 and implications for evolutionary origins. Genomics. 2000; 68: 101105.

3. 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.

4. Leiper J, Murray-Rust J, McDonald N, Vallance P. S-nitrosylation of dimethylarginine dimethylaminohydrolaseregulates enzyme activity: further interactions between nitric oxide synthase and dimethylargininedimethylaminohydrolase. Proc Natl Acad Sci U S A. 2002; 99: 1352713532.

5. Boger RH, Bode-Boger SM, Tsao PS, Lin PS, Chan JR, Cooke JP. An endogenous inhibitor of nitric oxide synthaseregulates endothelial adhesiveness for monocytes. J Am Coll Cardiol. 2000; 36: 22872295.

6. Cayatte AJ, Palacino JJ, Horten K, Cohen RA. Chronic inhibition of nitric oxide production accelerates neointimaformation and impairs endothelial function in hypercholesterolemic rabbits. Arterioscler Thromb. 1994; 14: 753759.

7. John P. Cooke Does ADMA Cause Endothelial Dysfunction? Arterioscler. Thromb. Vasc. Biol., 2000; 20: 2032 2037.

8. Vallance P. , Leiper J. Cardiovascular Biology of the Asymmetric Dimethylarginine:DimethylarginineDimethylaminohydrolase PathwayArterioscler. Thromb. Vasc. Biol., 2004; 24.

9. 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 orhypercholesterolemia. Arterioscler Thromb Vasc Biol. 2000; 20: 15571564.

10. Goonasekera CD, Rees DD, Woolard P, Frend A, Shah V, Dillon MJ. Nitric oxide synthase inhibitors andhypertension in children and adolescents. J Hypertens. 1997; 15: 901909.

11. Xiong Y, Fu YF, Fu SH, Zhou HH. Elevated levels of the serum endogenous inhibitor of nitric oxide synthaseand metabolic control in rats with streptozotocin-induced diabetes. J Cardiovasc Pharmacol. 2003; 42: 191196.

12. Stuhlinger MC, Tsao PS, Her JH, Kimoto M, Balint RF, Cooke JP. Homocysteine impairs the nitric oxide synthasepathway: role of asymmetric dimethylarginine. Circulation. 2001; 104: 25692575.

13. 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: 161167

14. Miyazaki H, Matsuoka H, Cooke JP, Usui M, Ueda S, Okuda S, Imaizumi T. Endogenous nitric oxide synthaseinhibitor: a novel marker of atherosclerosis. Circulation. 1999; 99: 11411146

References


ADMA = vascular NO

3 therapeutic

Strategies

Rduction ADMA-NOs

inhibition ADMA levels reduction NO synthase stimulation

L-ARGININE32,33L-ARGININE32,33

Retinoic Acid34

ThiazolidinedionesEstrogens35

Metformine

Retinoic Acid34

ThiazolidinedionesEstrogens35

Metformine Tetrahydrobiopterin

(BH4)

Tetrahydrobiopterin

(BH4)

Release

NOs by

reducing

caveolin

Reduces O2-

& ADMA

NOs

uncoupling

StatinsStatins

Treatment

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15. Elesber AA, Solomon H, Lennon RJ Coronary endothelial dysfunction is associated with erectile dysfunction andelevated asymmetric dimethylarginine in patients with early atherosclerosis. Eur Heart J;2006.

16. Solomon H, Lennon RJ Elevation of asymmetrical dimethylarginine (ADMA) and coronary artery disease in men witherectile dysfunction. Eur Urol; 2005 48(6):1004-11; discussion 1011-2.

17. Mathew V, Prasad A, Pumper G, Nelson RE, McConnell JP, Asymmetric dimethyl arginine levels correlate withcardiovascular risk factors in patients with erectile dysfunction. Atherosclerosis;2006 185(2):421-425.

18. Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of nitric oxidesynthesis in chronic renal failure. Lancet. 1992; 339: 572576.

19. Fermo I, Frolich J, Boger R. Plasma concentration of asymmetrical dimethylarginine and mortality in patients withend-stage renal disease: a prospective study. Lancet. 2001; 358: 21132117.

20. Usui M, Matsuoka H, Miyazaki H, Ueda S, Okuda S. Imaizumi T. Increased endogenous nitric oxide synthaseinhibitor in patients with congestive heart failure. Life Sci. 1998; 62: 24252430.

21. Saitoh M, Osanai T, Kamada T, Matsunaga T, Ishizaka H, Hanada H, Okumura K. High plasma level ofasymmetric dimethylarginine in patients with acutely exacerbated congestive heart failure: role in reduction of plasmanitric oxide level. Heart Vessels. 2003; 18: 177182.

22. Gorenflo M, Zheng C, Werle E, Fiehn W, Ulmer HE. Plasma levels of asymmetrical dimethyl-L-arginine in patientswith congenital heart disease and pulmonary hypertension. J Cardiovasc Pharmacol. 2001; 37: 489492

23. Millatt LJ, Whitley GS, Li D, Leiper JM, Iragy HM, Carey RM, Johns RA. Evidence for dysregulation ofdimethylarginine dimethylaminohydrolase I in chronic hypoxia-induced pulmonary hypertension. Circulation. 2003;108: 14931498

24. Holden DP, Fickling SA, Whitley GS, NusseySS. Plasma concentrations of asymmetric dimethylarginine, a naturalinhibitor of nitric oxide synthase, in normal pregnancy and preeclampsia. Am J Obstet Gynecol. 1998; 178: 551556

25. Savvidou M, Hingorani A, Tsikas D, Frolich J, Vallance P, Nicolaides K. Endothelial dysfunction and raisedplasma concentrations of asymmetric dimethylarginine in pregnant women who subsequently develop pre-eclampsia.Lancet. 2003; 361: 15111517

26. Zeiher AM, Drexler H, Saurbier B, Just H. Endothelium-mediated coronary blood flow modulation in humans: effectsof age, atherosclerosis, hypercholesterolemia, and hypertension. J Clin Invest. 1993;92:652662

27. 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 CollCardiol. 1994; 24: 471476

28. Xu D, Neville R, Finkel T. Homocysteine accelerates endothelial cell senescence. FEBS Lett. 2000; 470: 2024.

29. Rivard A, Fabre JE, Silver M, Chen D, Murohara T, Kearney M, Magner M, Asahara T, Isner JM. Age-dependentimpairment of angiogenesis. Circulation. 1999;99:111120

30. Vasa M, Breitschopf K, Zeiher AM, Dimmeler S. Nitric oxide activates telomerase and delays endothelial cellsenescence. Circ Res. 2000; 87: 540542

31. Fortunato Scalera, Jrgen Borlak, Bibiana Beckmann, Jens Martens-Lobenhoffer, Thomas Thum, MichaelTger, and Stefanie M. Bode-Bger Endogenous Nitric Oxide Synthesis Inhibitor Asymmetric Dimethyl L-ArginineAccelerates Endothelial Cell Senescence Arterioscler. Thromb. Vasc. Biol.:2004; 24: 1816 - 1822.

32. Gregor Theilmeier, Jason R. Chan, Christoff Zalpour, Barbara Anderson, Bing-yin Wang, Andreas Wolf, PhilipS. Tsao, John P. Cooke Adhesiveness of Mononuclear Cells in Hypercholesterolemic Humans Is Normalized byDietary L-Arginine Arterioscler. Thromb. Vasc. Biol., 1997; 17: 3557

33. Boger RH, Bode-Boger SM, Thiele W, Creutzig A, Alexander K, Frolich JC. Restoring vascular nitric oxideformation by L-arginine improves the symptoms of intermittent claudication in patients with peripheral arterial occlusivedisease. J Am Coll Cardiol. 1998; 32: 13361344

34. Achan V, Tran CT, Arrigoni F, Leiper JM, Vallance P. All-trans-retinoic acid increases nitric oxide synthesis byendothelial cells: a role for the induction of dimethylarginine dimethylaminohydrolase. Circ Res. 2002; 90: 764769

35. Holden DP, Cartwright JE, NusseySS, Whitley GS. Estrogen stimulates dimethylarginine dimethylaminohydrolaseactivity and the metabolism of symmetric dimethylarginine. Circulation. 2003; 108: 15751580.


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