title: Long-term methylglyoxal treatment causes endothelial dysfunction of rat isolated mesenteric artery.
abstract: Methylglyoxal (MGO) is a metabolite of glucose and likely related to pathogenesis of diabetes-related vascular complications including hypertension. In this study, long-term effects of MGO on endothelial function were examined. Rat isolated mesenteric artery was treated for 3 days with MGO using an organ culture method. The contractility, morphology and protein expression of organ-cultured artery were examined. MGO (42 µM, 3 days) impaired acetylcholine (ACh: 1 nM-300 µM)-induced endothelium-dependent relaxation, while it had no effect on sodium nitroprusside (0.1 nM-10 µM)-induced endothelium-independent relaxation. MGO decreased ACh (3 µM)-induced nitric oxide (NO) production as measured by a fluorescence NO indicator, diaminofluorescein-2. Consistently, MGO inhibited ACh (3 µM)-induced phosphorylation of vasodilator stimulated phosphoprotein (an indicator of cyclic GMP production). MGO induced apoptosis in endothelium as detected by TdT-mediated dUTP-biotin nick-end labeling staining. MGO induced accumulation of superoxide in endothelium as detected by dihydroethidium staining. MGO decreased protein expression of endothelial NO synthase (eNOS). Gp91ds-tat (0.1 µM), an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), prevented the impairment of endothelium-dependent relaxation and the decrease in eNOS protein caused by MGO. The present results demonstrated that long-term MGO treatment impairs endothelium-dependent relaxation through NOX-derived increased superoxide-mediated endothelial apoptosis.
authors.affiliation: Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Aomori, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Mukohda
authors.forename: Tomoka
authors.initials: T
authors.lastname: Morita
authors.forename: Muneyoshi
authors.initials: M
authors.lastname: Okada
authors.forename: Yukio
authors.initials: Y
authors.lastname: Hara
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yamawaki
mesh_terms: D000109:Acetylcholine; D000199:Actins; D000818:Animals; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D009569:Nitric Oxide; D009599:Nitroprusside; D011765:Pyruvaldehyde / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000199:Actins; D009599:Nitroprusside; D009569:Nitric Oxide; D011765:Pyruvaldehyde; D000109:Acetylcholine