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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.

SUBMITTER: Liu H

PROVIDER: S-EPMC6349192 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Vildagliptin improves high glucose-induced endothelial mitochondrial dysfunction via inhibiting mitochondrial fission.

Liu Hengdao H Xiang Hong H Zhao Shaoli S Sang Haiqiang H Lv Fenghua F Chen Ruifang R Shu Zhihao Z Chen Alex F AF Chen Shuhua S Lu Hongwei H

Journal of cellular and molecular medicine 20181116 2

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 microscop ...[more]

PMID: 30444033

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Project description:The damage of vascular endothelial barrier function induced by sepsis is critical in causing multiple organ dysfunctions. Previous studies showed that dexmedetomidine (Dex) played a vital role in protecting organ functions. However, whether Dex participates in protecting vascular leakage of sepsis and the associated underlying mechanism remains unknown yet. We used cecal ligation and puncture induced septic rats and lipopolysaccharide stimulated vascular endothelial cells (VECs) to establish models in vivo and in vitro, then the protective effects of Dex on the vascular endothelial barrier function of sepsis were observed, meanwhile, related mechanisms on regulating mitochondrial fission were further studied. The results showed that Dex could significantly reduce the permeability of pulmonary veins and mesenteric vessels, increase the expression of intercellular junction proteins, enhance the transendothelial electrical resistance and decrease the transmittance of VECs, accordingly protected organ functions and prolonged survival time in septic rats. Besides, the mitochondria of VECs were excessive division after sepsis, while Dex could significantly inhibit the mitochondrial fission and protect mitochondrial function by restoring mitochondrial morphology of VECs. Furthermore, the results showed that ER-MITO contact sites of VECs were notably increased after sepsis. Nevertheless, Dex reduced ER-MITO contact sites by regulating the polymerization of actin via α2 receptors. The results also found that Dex could induce the phosphorylation of the dynamin-related protein 1 through down-regulating extracellular signal-regulated kinase1/2, thus playing a role in the regulation of mitochondrial division. In conclusion, Dex has a protective effect on the vascular endothelial barrier function of septic rats. The mechanism is mainly related to the regulation of Drp1 phosphorylation of VECs, inhibition of mitochondrial division by ER-MITO contacts, and protection of mitochondrial function.

Project description:AimsSphingosine-1-phosphate receptor 2 (S1PR2) is a G-protein-coupled receptor that regulates sphingosine-1-phosphate-triggered cellular response. However, the role of S1PR2 in diabetes-induced glomerular endothelial cell dysfunction remains unclear. This study aims to investigate the effect of S1PR2 blockade on the morphology and function of mitochondria in human renal glomerular endothelial cells (HRGECs).MethodsHRGECs were pretreated with a S1PR2 antagonist (JTE-013) or a Rho-associated coiled coil-containing protein kinase 1 (ROCK1) inhibitor (Y27632) for 30 min and then cultured with normal glucose (5.5 mM) or high glucose (30 mM) for 72 h. The protein expression levels of RhoA, ROCK1, and Dynmin-related protein-1(Drp1) were evaluated by immunoblotting; mitochondrial morphology was observed by electron microscopy; intracellular levels of ATP, ROS, and Ca2+ were measured by ATPlite, DCF-DA, and Rhod-2 AM assays, respectively. Additionally, the permeability, apoptosis, and migration of cells were determined to evaluate the effects of S1PR2 and ROCK1 inhibition on high glucose-induced endothelial dysfunction.ResultsHigh glucose induced mitochondrial fission and dysfunction, indicated by increased mitochondrial fragmentation, ROS generation, and calcium overload but decreased ATP production. High glucose also induced endothelial cell dysfunction, indicated by increased permeability and apoptosis but decreased migration. However, inhibition of either S1PR2 or ROCK1 almost completely blocked these high glucose-mediated cellular responses. Furthermore, inhibiting S1PR2 resulted in the deceased expression of RhoA, ROCK1, and Drp1 while inhibiting ROCK1 led to the downregulated expression of Drp1.ConclusionsS1PR2 antagonist modulates the morphology and function of mitochondria in HRGECs via the positive regulation of the RhoA/ROCK1/Drp1 signaling pathway, suggesting that the S1PR2/ROCK1 pathway may play a crucial role in high glucose milieu.

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Vildagliptin improves high glucose-induced endothelial mitochondrial dysfunction via inhibiting mitochondrial fission.

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Vildagliptin improves high glucose-induced endothelial mitochondrial dysfunction via inhibiting mitochondrial fission.

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