Attenuation of hypertension development by scavenging methylglyoxal in fructose-treated rats.
OBJECTIVE
Methylglyoxal is a reactive dicarbonyl intermediate of metabolism produced in the body. It reacts with certain proteins and forms damaging advanced glycation endproducts (AGEs) such as N epsilon-carboxyethyl-lysine (CEL) and N epsilon-carboxymethyl-lysine (CML). Increased methylglyoxal levels are found in diabetes mellitus and associated with hypertension development in the spontaneously hypertensive rats (SHR). The purpose of this study was to investigate whether increased endogenous formation of methylglyoxal and methylglyoxal-induced AGEs caused hypertension development in normotensive Sprague Dawley rats.


METHODS
The rats were fed chronically for 16 weeks with fructose, a known precursor of methylglyoxal formation. One group of rats was cotreated with fructose and metformin, an AGEs formation inhibitor. Methylglyoxal and reduced glutathione (GSH) were measured by high performance liquid chromatography, whereas hydrogen peroxide was measured by a dicholorofluorescin assay. Immunohistochemistry was performed for endothelial nitric oxide synthase (eNOS), CEL and CML.


RESULTS
Fructose-fed rats had elevated blood pressure, serum methylglyoxal and triglycerides and reduced serum levels of GSH. Methylglyoxal, hydrogen peroxide and CEL were increased in the aorta, whereas eNOS was reduced. CEL and CML were also increased in the mesenteric artery endothelium along with media/lumen ratio, signifying structural remodelling. All the harmful changes in fructose-fed rats were attenuated in metformin and fructose cotreated rats.


CONCLUSIONS
Increased methylglyoxal, AGEs, oxidative stress and reduced eNOS along with structural remodeling of the vessel wall in the aorta and mesenteric artery likely play a role in the pathogenesis of hypertension.
Wang
Xiaoxia
X
Department of Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Jia
Xuming
X
Chang
Tuanjie
T
Desai
Kaushik
K
Wu
Lingyun
L
D000818:Animals; D001011:Aorta / Q000378:metabolism; D004040:Dietary Carbohydrates / Q000494:pharmacology; D005632:Fructose / Q000494:pharmacology*; D005978:Glutathione / Q000097:blood; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D018384:Oxidative Stress / Q000502:physiology; D011765:Pyruvaldehyde / Q000097:blood*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004040:Dietary Carbohydrates; D017127:Glycation End Products, Advanced; D007004:Hypoglycemic Agents; D005632:Fructose; C048496:N(6)-carboxymethyllysine; D011765:Pyruvaldehyde; D008687:Metformin; D006861:Hydrogen Peroxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D005978:Glutathione; D008239:Lysine