Downregulation of the GLP-1/CREB/adiponectin pathway is partially responsible for diabetes-induced dysregulated vascular tone and VSMC dysfunction

Abstract

BackgroundThe dysfunction of vasculature is observed in diabetes and might be responsible for the increased incidence of vascular events. Previous studies indicated that supplementation of GLP-1 analogues is beneficial to the cardiovascular functions in diabetic patients, but the mechanisms are not clear. MethodsA type 1 diabetic model was constructed. Vascular constrictions were measured using wire myograph. Western blotting and quantitative PCR were adopted to analyze the expression profiles of key molecules. Mitochondrial functions were analyzed in both vascular tissues or vascular smooth muscle cells (VSMCs). Dual-luciferase reporter assay was used to investigate the mechanism of adiponectin regulation. ResultsIn this study, abnormal vascular hypertrophy and increased vascular tones were observed in both diabetic patients and animals. ROS productions were increased in vessels and VSMCs from diabetic patients and animals, and the ROS scavenger mitoTEMPO partially attenuated the abnormal vascular tones and hypertension. In addition, decreased GLP-1 levels were observed, while GLP-1 supplementation improved the mitochondrial functions and vascular tones. Furthermore, it was shown that GLP-1 supplementation enhanced adiponectin expressions, while adiponectin facilitated the phosphorylation of AMPK and Sirt1 expressions. Also, CREB phosphorylation was enhanced upon GLP-1 supplementation and promoted the transcriptions of adiponectin. Finally, CREB inhibition partially attenuated the effects of GLP-1 on mitochondrial functions and adiponectin expressions. ConclusionGLP-1 downregulation might be an important mechanism of abnormal mitochondrial function and vascular tone in diabetes. Targeting GLP-1/CREB/adiponectin axis might become a promising therapeutic strategy in alleviating diabetes-related cardiovascular dysfunctions.