Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase.
BACKGROUND
An endogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine (ADMA), is elevated in patients with type 2 diabetes mellitus (DM). This study explored the mechanisms by which ADMA becomes elevated in DM.


RESULTS
Male Sprague-Dawley rats were fed normal chow or high-fat diet (n=5 in each) with moderate streptozotocin injection to induce type 2 DM. Plasma ADMA was elevated in diabetic rats (1.33+/-0.31 versus 0.48+/-0.08 micromol/L; P<0.05). The activity, but not the expression, of dimethylarginine dimethylaminohydrolase (DDAH) was reduced in diabetic rats and negatively correlated with their plasma ADMA levels (P<0.05). DDAH activity was significantly reduced in vascular smooth muscle cells and human endothelial cells (HMEC-1) exposed to high glucose (25.5 mmol/L). The impairment of DDAH activity in vascular cells was associated with an accumulation of ADMA and a reduction in generation of cGMP. In human endothelial cells, coincubation with the antioxidant polyethylene glycol-conjugated superoxide dismutase (22 U/mL) reversed the effects of the high-glucose condition on DDAH activity, ADMA accumulation, and cGMP synthesis.


CONCLUSIONS
A glucose-induced impairment of DDAH causes ADMA accumulation and may contribute to endothelial vasodilator dysfunction in DM.
Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, Calif 94305, USA.
Ken Y
KY
Lin
Akira
A
Ito
Tomoko
T
Asagami
Philip S
PS
Tsao
Shanthi
S
Adimoolam
Masumi
M
Kimoto
Hideaki
H
Tsuji
Gerald M
GM
Reaven
John P
JP
Cooke
D000581:Amidohydrolases / Q000502:physiology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001011:Aorta / Q000201:enzymology; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000097:blood; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D018384:Oxidative Stress; D011092:Polyethylene Glycols / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000494:pharmacology
D000975:Antioxidants; D004791:Enzyme Inhibitors; D011092:Polyethylene Glycols; C024917:symmetric dimethylarginine; C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; C063471:polyethylene glycol-superoxide dismutase; D000581:Amidohydrolases; C059999:dimethylargininase; D006152:Cyclic GMP; D005947:Glucose