Repeated Glucose Spikes and Insulin Resistance Synergistically Increase Endothelial Function Vulnerability to High Glucose Levels through Redox Imbalance, and Bardoxolone Methyl (CDDO-Me) Ameliorates Endothelial Dysfunction

BackgroundGlucose spikes (GSs) observed after a meal in metabolic syndrome have been reported to cause endothelial dysfunction. However, other insulin resistance-related factors can affect GS-induced endothelial dysfunction. To eliminate these confounding factors, we investigated the separate and combined effects of GSs and insulin resistance due to diet-induced obesity on endothelial function and clarified whether bardoxolone methyl (CDDO-Me), a novel nuclear factor erythroid 2-related factor 2 (Nrf2) activator, protects against GS-induced endothelial dysfunction.MethodsIn the first cohort, eight-week-old male Wistar rats were assigned to one of four groups: 1) control diet (CD)-GS (-); 2) CD-GS (+); 3) Western-type diet (WTD)-GS (-); and 4) WTD-GS (+). Rats were fed a CD or WTD for 13 weeks and intraperitoneally injected with saline or glucose for 1 week twice daily at 20 weeks of age. In the second cohort, four groups from the first cohort were additionally divided into vehicle and CDDO-Me (3 mg/kg) groups. At 21 weeks of age, endothelial function was evaluated using isolated thoracic aortas under normal (5.5 mM) and high-glucose (20 mM) conditions. Gene expression was analyzed, and superoxide anion was evaluated by dihydroethidium (DHE) staining of aortas.ResultsIn the first cohort, endothelium-dependent relaxation (EDR) in the CD-GS (+) or WTD-GS (-) group was comparable to that in the CD-GS (-) group, but it deteriorated in the WTD-GS (+) group only under high-glucose conditions. Antioxidant agents, such as superoxide dismutase, catalase, apocynin (a NOX inhibitor) and Mito-TEMPO (a mitochondrial-targeted superoxide scavenger), improved endothelial function. In this group, upregulation of NOX2 expression and downregulation of SOD2 and catalase expression were observed in the aortas, and DHE intensity was enhanced. In the second cohort, pretreatment of the WTD-GS (+) group with CDDO-Me attenuated this endothelial dysfunction accompanied by a correction of redox imbalance in gene expression and an attenuation of DHE intensity.ConclusionWe demonstrated that GSs and insulin resistance synergistically increased endothelial function vulnerability to high-glucose levels through redox imbalance, although each factor alone had little effect on endothelial function. Furthermore, we showed that pretreatment with CDDO-Me ameliorated endothelial dysfunction caused by GSs in metabolic syndrome model rats.