Abstract
Evidence has been provided linking microRNAs (miRNAs) and diabetic complications, by the regulation of molecular pathways, including insulin-signaling, involved in the pathophysiology of vascular dysfunction. Methylglyoxal (MGO) accumulates in diabetes and is associated with cardiovascular complications. This study aims to analyze the contribution of miRNAs in the MGO-induced damaging effect on insulin responsiveness in mouse aortic endothelial cells (MAECs). miRNA modulation was performed by transfection of specific miRNA mimics and inhibitors in MAECs, treated or not with MGO. miRNA-target protein levels were evaluated by Western blot. PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2) regulation by miR-214 was tested by luciferase assays and by the use of a target protector specific for miR-214 on PHLPP2-3′UTR. This study reveals a 4-fold increase of PHLPP2 in MGO-treated MAECs. PHLPP2 levels inversely correlate with miR-214 modulation. Moreover, miR-214 overexpression is able to reduce PHLPP2 levels in MGO-treated MAECs. Interestingly, a direct regulation of PHLPP2 is proved to be dependent by miR-214. Finally, the inhibition of miR-214 impairs the insulin-dependent Akt activation, while its overexpression rescues the insulin effect on Akt activation in MGO-treated MAECs. In conclusion, this study shows that PHLPP2 is a target of miR-214 in MAECs, and identifies miR-214 downregulation as a contributing factor to MGO-induced endothelial insulin-resistance.
Highlights
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by defects in both β-cell function and insulin sensitivity, which result in elevated blood glucose levels [1]
We have found that the expression of other three miRNAs is related to diabetes: miR-214, miR-450a, and miR-126 are reduced by 32%, 22%, and 30%, respectively, in mouse aortic endothelial cells (MAECs) exposed to MGO [21]
In order to evaluate the possible contribution of miRNAs to insulin signal transduction, found to be altered in MAECs exposed to MGO [18], a combination of available algorithms has been considered, and a comprehensive atlas of the putative miRNA binding site predictions has been consulted using the mirWalk database
Summary
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by defects in both β-cell function and insulin sensitivity, which result in elevated blood glucose levels [1]. Insulin-induced NO production enhances smooth muscle vasodilation and blood flow, which are impaired in the insulin-resistant state [5]. Given the vasotropic functions of insulin in endothelial cells, endothelial insulin resistance results in an impaired endothelial-dependent vasodilation, which represents a common feature of endothelial dysfunction in diabetic patients, and an important cause of complications, responsible for the high mortality associated to T2DM [6]. There is a critical need to better understand the underlying mechanisms responsible for the endothelial insulin resistance, in order to develop new and improved therapeutic strategies for these chronic conditions
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