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(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
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.
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).
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
ADMA
Dimethylamine + Citrulline
Renal Excretion
80 %
20 %
100 %
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
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
Promotes Promotes media media Smooth muscle Smooth muscle cells cells proliferation proliferation
NO
induces induces vasospasmi vasospasmi Increases Increases endothelial-cell endothelial-cell adhesiveness adhesiveness
Fig. 8 Molecular Mcanisms and cellular molecular caused by the diminution of NO production Laboratoire Philippe Auguste
+ + --
+ +
smoking Tabagisme
Tabagisme
Ob Obesity Ob sit sit Hypercholest hypercholesterolemia Hypercholest rol rol mie mie
Hypertension Hypertension
Fig. 9 Risk factors that make endothelial dysfunction with augmentation of ADMA and diminution of NO production
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 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
NO synthase stimulation Reduces O2& ADMA NOs uncoupling Release NOs by reducing caveolin
34 Retinoic Retinoic Acid Acid34 Thiazolidinediones Thiazolidinediones 35 Estrogens Estrogens35 Metformine Metformine
Statins Statins
References
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