Aminoguanidine normalizes ET-1-induced aortic contraction in type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats by suppressing Jab1-mediated increase in ETA-receptor expression

作者：Nemoto Shingo; Taguchi Kumiko; Matsumoto Takayuki; Kamata Katsuo; Kobayashi Tsuneo^*

来源：Peptides, 2012, 33(1): 109-119.

DOI：10.1016/j.peptides.2011.11.018

• Diabetes
• Endothelin-1
• ETA-R
• Jab1
• O-GlcNAc
• Otsuka Long-Evans Tokushima Fatty rat

Circulating levels of endothelin (ET)-1 are increased in the diabetic state, as is endogenous ETA-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 HIF1 alpha/ECE1/plasma ET-1 and plasma CML-AGEs were increased, (3) the ET-1-stimulated ERR phosphorylation mediated by ETA-R was increased, (4) the expression level of Jab1-modified ETA-R protein was reduced, and (5) the expression level of O-GlcNAcylated ETA-R protein was increased. Aortas isolated from such OLETF rats that had been treated with AG (50 mg/kg/day for 10 weeks) exhibited reduced ET-1-induced contraction, suppressed ET-1-stimulated ERR phosphorylation accompanied by down-regulation of ETA-R, and increased modification of ETA-R by Jab1. Such AG-treated rats exhibited normalized plasma ET-1 and CML-AGE levels, and their aortas exhibited decreased HIF1 alpha/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 ETA-R/ERK activities and/or by normalizing the imbalance between Jab1 and O-GlcNAc in type 2 diabetes.

• 出版日期2012-1
• 单位河北医科大学