pISSN 1226-4512 eISSN 2093-3827

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Original Article

Korean J Physiol Pharmacol 2021; 25(5): 425-437

Published online September 1, 2021 https://doi.org/10.4196/kjpp.2021.25.5.425

Copyright © Korean J Physiol Pharmacol.

Sitagliptin attenuates endothelial dysfunction independent of its blood glucose controlling effect

Xin-Miao Chang1,2, Fei Xiao3, Qi Pan1, Xiao-Xia Wang1, and Li-Xin Guo1,2,*

1Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, 2Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, 3The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, P. R. China

Correspondence to:Li-Xin Guo
E-mail: glxwork2016@163.com

Received: February 16, 2021; Revised: May 21, 2021; Accepted: May 24, 2021

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright © Korean J Physiol Pharmacol, pISSN 1226-4512, eISSN 2093-3827

Abstract

Although the contributions of sitagliptin to endothelial dysfunction in diabetes mellitus were previously reported, the mechanisms still undefined. Autophagy plays an important role in the development of diabetes mellitus, but its role in diabetic macrovascular complications is unclear. This study aims to observe the effect of sitagliptin on macrovascular endothelium in diabetes and explore the role of autophagy in this process. Diabetic rats were induced through administration of high-fat diet and intraperitoneal injection of streptozotocin. Then diabetic rats were treated with or without sitagliptin for 12 weeks. Endothelial damage and autophagy were measured. Human umbilical vein endothelial cells were cultured either in normal glucose or in high glucose medium and intervened with different concentrations of sitagliptin. Rapamycin was used to induce autophagy. Cell viability, apoptosis and autophagy were detected. The expressions of proteins in c-Jun N-terminal kinase (JNK)-Bcl-2-Beclin-1 pathway were measured. Sitagliptin attenuated injuries of endothelium in vivo and in vitro. The expression of microtubuleassociated protein 1 light chain 3 II (LC3II) and beclin-1 were increased in aortas of diabetic rats and cells cultured with high-glucose, while sitagliptin inhibited the over-expression of LC3II and beclin-1. In vitro pre-treatment with sitagliptin decreased rapamycin-induced autophagy. However, after pretreatment with rapamycin, the protective effect of sitagliptin on endothelial cells was abolished. Further studies revealed sitagliptin increased the expression of Bcl-2, while inhibited the expression of JNK in vivo. Sitagliptin attenuates injuries of vascular endothelial cells caused by high glucose through inhibiting over-activated autophagy. JNK-Bcl-2-Beclin-1 pathway may be involved in this process.

Keywords: Apoptosis, Autophagy, Human umbilical vein endothelial cell, Sitagliptin phosphate, Streptozotocin diabetes