Dipeptidyl peptidase‑4 inhibitor sitagliptin prevents high glucose‑induced apoptosis via activation of AMP‑activated protein kinase in endothelial cells

Wu,Chao; Hu,Shunying; Wang,Nanping; Tian,Jianwei

doi:10.3892/mmr.2017.6501

Dipeptidyl peptidase‑4 inhibitor sitagliptin prevents high glucose‑induced apoptosis via activation of AMP‑activated protein kinase in endothelial cells

Authors:
- Chao Wu
- Shunying Hu
- Nanping Wang
- Jianwei Tian
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Affiliations: Postgraduate Department, Third Military Medical University, Chongqing 400038, P.R. China, Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, P.R. China, Institute of Cardiovascular Science, Peking University, Beijing 100191, P.R. China, Department of Cardiology, Air Force General Hospital, Beijing 100142, P.R. China
Published online on: April 21, 2017 https://doi.org/10.3892/mmr.2017.6501
Pages: 4346-4351

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Abstract

Diabetes mellitus (DM), which is a chronic metabolic disorder, is the primary risk factor of life‑threatening vascular complications. Endothelial apoptosis is important in the development of the initial vascular lesion preceding the diabetic disease. Sitagliptin is a dipeptidyl peptidase‑4 (DPP‑4) inhibitor and extensively used in the clinical treatment of DM. DPP‑4 inhibitors have been demonstrated to be beneficial in the improvement of endothelial homeostasis, however the molecular mechanism by which they exhibit these effects remains to be elucidated. The effect of sitagliptin on endothelial apoptosis was examined in cultured human umbilical vein endothelial cells (HUVECs) incubated with high glucose (HG). The present study demonstrated that treatment of HUVECs with HG increased reactive oxygen species (ROS) production, stimulated mitochondrial depolarization and resulted in cell apoptosis. Pretreatment of HUVECs with sitagliptin significantly prevented HG‑induced endothelial apoptosis. It was further demonstrated that sitagliptin effectively inhibited ROS generation and mitochondrial membrane potential collapse. Similarly, adenosine monophosphate‑activated protein kinase (AMPK) activation by sitagliptin protected against HG‑induced ROS production, mitochondrial membrane potential collapse and endothelial cell apoptosis, as detected via western blotting and flow cytometry analysis. The present study therefore revealed a novel mechanism of sitagliptin‑mediated AMPK activation in preventing endothelial apoptosis and indicated the therapeutic potential of sitagliptin in vascular complications associated with endothelial apoptosis.

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