Methylglyoxal and methylglyoxal-arginine adducts do not directly inhibit endothelial nitric oxide synthase.
Increased formation of the reactive dicarbonyl compound methylglyoxal (MGO) and MGO-derived advanced glycation end products (AGEs) seems to be implicated in endothelial dysfunction and the development of diabetic vascular complications. MGO reacts with arginine residues in proteins to generate the major glycated adducts 5-hydro-5-methylimidazolone (MG-H1) and argpyrimidine (AP). We investigated whether the free forms of these adducts contribute to vascular cell dysfunction by inhibition of endothelial nitric oxide synthase (eNOS). MG-H1 and AP were synthesized and purified by reversed-phase chromatography, and the conversion of labeled L-arginine to L-citrulline was used to monitor eNOS activity. In contrast to the endogenous eNOS inhibitor asymmetric dimethylarginine (half maximal inhibitory concentration, approximately 5 micromol/L), pathophysiological concentrations of MGO and MG-H1 and AP did not inhibit eNOS activity. Although MGO-derived AGEs are implicated in the development of diabetic vascular complications, this study indicates that this is not mediated via direct inhibition of eNOS activity.
Brouwers
Olaf
O
Department of Internal Medicine, Division of General Internal Medicine, Laboratory for Metabolism and Vascular Medicine, Maastricht University, Maastricht, the Netherlands.
Teerlink
Tom
T
van Bezu
Jan
J
Barto
Rob
R
Stehouwer
Coen D A
CD
Schalkwijk
Casper G
CG
D000873:Anthracenes / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors*; D011407:Propane / Q000031:analogs & derivatives / Q000494:pharmacology; D011765:Pyruvaldehyde / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014471:Umbilical Veins / Q000201:enzymology*
D000873:Anthracenes; D004791:Enzyme Inhibitors; C018524:N,N-dimethylarginine; D011765:Pyruvaldehyde; D001120:Arginine; D052250:Nitric Oxide Synthase Type III; D011407:Propane