title: Aminoguanidine normalizes ET-1-induced aortic contraction in type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats by suppressing Jab1-mediated increase in ET(A)-receptor expression.
abstract: Circulating levels of endothelin (ET)-1 are increased in the diabetic state, as is endogenous ET(A)-receptor-mediated vasoconstriction. However, the responsible mechanisms remain unknown. We hypothesized that ET-1-induced vasoconstriction is augmented in type 2 diabetes with hyperglycemia through an increment in advanced glycation end-products (AGEs). So, we investigated whether treatment with aminoguanidine (AG), an inhibitor of AGEs, would normalize the ET-1-induced contraction induced by ET-1 in strips of thoracic aortas isolated from OLETF rats at the chronic stage of diabetes. In such aortas (vs. those from age-matched genetic control LETO rats): (1) the ET-1-induced contraction was enhanced, (2) the levels of HIF1α/ECE1/plasma ET-1 and plasma CML-AGEs were increased, (3) the ET-1-stimulated ERK phosphorylation mediated by ET(A)-R was increased, (4) the expression level of Jab1-modified ET(A)-R protein was reduced, and (5) the expression level of O-GlcNAcylated ET(A)-R protein was increased. Aortas isolated from such OLETF rats that had been treated with AG (50mg/kg/day for 10 weeks) exhibited reduced ET-1-induced contraction, suppressed ET-1-stimulated ERK phosphorylation accompanied by down-regulation of ET(A)-R, and increased modification of ET(A)-R by Jab1. Such AG-treated rats exhibited normalized plasma ET-1 and CML-AGE levels, and their aortas exhibited decreased HIF1α/ECE1 expression. However, such AG treatment did not alter the elevated levels of plasma glucose or insulin, or systolic blood pressure seen in OLETF rats. These data from the OLETF model suggest that within the timescale studied here, AG normalizes ET-1-induced aortic contraction by suppressing ET(A)-R/ERK activities and/or by normalizing the imbalance between Jab1 and O-GlcNAc in type 2 diabetes.
authors.affiliation: Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Nemoto
authors.forename: Kumiko
authors.initials: K
authors.lastname: Taguchi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Katsuo
authors.initials: K
authors.lastname: Kamata
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Kobayashi
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001786:Blood Glucose / Q000032:analysis; D001794:Blood Pressure / Q000187:drug effects; D000075686:COP9 Signalosome Complex; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000503:physiopathology*; D015232:Dinoprostone / Q000494:pharmacology; D019332:Endothelin-1 / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D016232:Endothelins / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors; D006146:Guanidines / Q000494:pharmacology*; D066298:In Vitro Techniques; D007328:Insulin / Q000097:blood; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D020334:Rats, Inbred OLETF; D044022:Receptor, Endothelin A / Q000378:metabolism*; D044023:Receptor, Endothelin B / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D001786:Blood Glucose; D019332:Endothelin-1; D016232:Endothelins; D017127:Glycation End Products, Advanced; C490121:Gps1 protein, rat; D006146:Guanidines; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D010446:Peptide Fragments; D011506:Proteins; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C074308:sovateltide; D010656:Phenylephrine; D048049:Extracellular Signal-Regulated MAP Kinases; D000075686:COP9 Signalosome Complex; D015232:Dinoprostone; C004479:pimagedine; D000117:Acetylglucosamine