Methylglyoxal scavengers attenuate endothelial dysfunction induced by methylglyoxal and high concentrations of glucose.
OBJECTIVE
Endothelial dysfunction is a feature of hypertension and diabetes. Methylglyoxal (MG) is a reactive dicarbonyl metabolite of glucose and its levels are elevated in spontaneously hypertensive rats and in diabetic patients. We investigated if MG induces endothelial dysfunction and whether MG scavengers can prevent endothelial dysfunction induced by MG and high glucose concentrations.


METHODS
Endothelium-dependent relaxation was studied in aortic rings from Sprague-Dawley rats. We also used cultured rat aortic and human umbilical vein endothelial cells. The MG was measured by HPLC and Western blotting and assay kits were used.


RESULTS
Incubation of aortic rings with MG (30 µM) or high glucose (25 mM) attenuated endothelium-dependent, acetylcholine-induced relaxation, which was restored by two different MG scavengers, aminoguanidine (100 µM) and N-acetyl cysteine (NAC) (600 µM). Treatment of cultured endothelial cells with MG or high glucose increased cellular MG levels, effects prevented by aminoguanidine and NAC. In cultured endothelial cells, MG and high glucose reduced basal and bradykinin-stimulated nitric oxide (NO) production, cGMP levels, and serine-1177 phosphorylation and activity of endothelial NO synthase (eNOS), without affecting threonine-495 and Akt phosphorylation or total eNOS protein. These effects of MG and high glucose were attenuated by aminoguanidine or NAC.


CONCLUSIONS
Our results show for the first time that MG reduced serine-1177 phosphorylation, activity of eNOS and NO production. MG caused endothelial dysfunction similar to that induced by high glucose. Specific and safe MG scavengers have potential to prevent endothelial dysfunction induced by MG and high glucose concentrations.
Dhar
Arti
A
Department of Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
Dhar
Indu
I
Desai
Kaushik M
KM
Wu
Lingyun
L
D000109:Acetylcholine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005947:Glucose / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D006146:Guanidines / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011765:Pyruvaldehyde / Q000009:adverse effects / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D014652:Vascular Diseases / Q000378:metabolism / Q000517:prevention & control*; D014664:Vasodilation / Q000187:drug effects*
D006146:Guanidines; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D011765:Pyruvaldehyde; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; D005947:Glucose; D000109:Acetylcholine; C004479:pimagedine; D000111:Acetylcysteine
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