Vildagliptin improves high glucose‐induced endothelial mitochondrial dysfunction via inhibiting mitochondrial fission

Abstract

The dipeptidyl peptidase 4 inhibitor vildagliptin (VLD), a widely used anti‐diabetic drug, exerts favourable effects on vascular endothelium in diabetes. We determined for the first time the improving effects of VLD on mitochondrial dysfunction in diabetic mice and human umbilical vein endothelial cells (HUVECs) cultured under hyperglycaemic conditions, and further explored the mechanism behind the anti‐diabetic activity. Mitochondrial ROS (mtROS) production was detected by fluorescent microscope and flow cytometry. Mitochondrial DNA damage and ATP synthesis were analysed by real time PCR and ATPlite assay, respectively. Mitochondrial network stained with MitoTracker Red to identify mitochondrial fragmentation was visualized under confocal microscopy. The expression levels of dynamin‐related proteins (Drp1 and Fis1) were determined by immunoblotting. We found that VLD significantly reduced mtROS production and mitochondrial DNA damage, but enhanced ATP synthesis in endothelium under diabetic conditions. Moreover, VLD reduced the expression of Drp1 and Fis1, blocked Drp1 translocation into mitochondria, and blunted mitochondrial fragmentation induced by hyperglycaemia. As a result, mitochondrial dysfunction was alleviated and mitochondrial morphology was restored by VLD. Additionally, VLD promoted the phosphorylation of AMPK and its target acetyl‐CoA carboxylase in the setting of high glucose, and AMPK activation led to a decreased expression and activation of Drp1. In conclusion, VLD improves endothelial mitochondrial dysfunction in diabetes, possibly through inhibiting Drp1‐mediated mitochondrial fission in an AMPK‐dependent manner.

Dihydromyricetin Improves Endothelial Dysfunction in Diabetic Mice via Oxidative Stress Inhibition in a SIRT3-Dependent Manner

“…SIRT3 is localized in mammalian mitochondria and deficiency of SIRT3 is detrimental to mitochondrial function. Mitochondrial oxidative stress leads to mtDNA damage and lower mtDNA copy number indicates serious mitochondrial dysfunction, contributing to endothelial dysfunction [ 31 , 32 ]. The results showed decreased mtDNA copy number in thoracic aorta of WT diabetic mice, which was markedly increased after DHY treatment.…”

AMPK, Mitochondrial Function, and Cardiovascular Disease

“…In the meantime, DRP1-S616 phosphorylation was decreased, while DRP1-S637 phosphorylation was increased, ultimately leading to mitochondrial fission [ 229 ]. Vildagliptin improved mitochondrial dysfunction in diabetic ECs, possibly by blunting DRP1-dependent mitochondrial fission by inducing AMPK activation [ 230 ]. Therefore, attenuation of mitochondrial fission by means of activating AMPK may represent a promising approach for macrovascular complications in diabetic patients.…”

Vasculoprotective Effects of Vildagliptin. Focus on Atherogenesis

“…Progression of these risk factors underlie the development of atherosclerosis and cardiovascular diseases [41]. Liu et al (2019) demonstrated that vildagliptin promotes NO (nitric oxide) production and restores physiological ROS synthesis deregulated under diabetic conditions. Vildagliptin also improves diabetes-induced mitochondrial dysfunction.…”

“…Drp1 and Fis1 (dynamin-related proteins) are essential regulators of mitochondrial fission. Diabetic state is characterized by significantly increased expression of Drp1 and Fis1 [17]. The usage of Drp1 inhibitor mdivi¬1 (mitochondrial division inhibitor 1) () inhibits cardiomyocyte cell death after cardiac arrest.…”

“…Vildagliptin has the ability to reduce the expression of Drp1 and Fis1 and, as a result, mitigates mitochondrial fragmentation induced by hyperglycemia. Decreased expression and activation of Drp1 has been probably caused by increased phosphorylation of AMPK (5'AMP-activated protein kinase) and its target acetyl-CoA carboxylase induced by vildagliptin [17]. In another study performed by Oeseburg et al (2010), the DPP-4 inhibitor significantly increased GLP-1 levels and limited reactive oxygen species-induced senescence of endothelial cells.…”