Department of Geriatric Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Division of Cardiology and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China.
Department of Geriatric Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Biochem Pharmacol. 2020 Jul;177:113951. doi: 10.1016/j.bcp.2020.113951. Epub 2020 Apr 3.
Dipeptidyl peptidase-4 (DPP4) is elevated in numerous cardiovascular pathological processes and DPP4 inhibition is associated with reduced inflammation and oxidative stress. The aim of this study was to examine the role of DPP4 in endothelial senescence. Sprague-Dawley rats (24 months) were orally administrated saxagliptin (10 mg·kg·d), a DPP4 inhibitor, for 12 weeks in drinking water. Body weight, heart rate, blood glucose, and blood pressure were measured and vascular histological experiments were performed. In vitro studies were performed using HO-induced senescent human umbilical vein endothelial cells. Both in vivo and in vitro studies confirmed the elevation of DPP4 in senescent vascular endothelium, and inhibition or knockdown of DPP4 ameliorated endothelial senescence. In addition, DPP4 inhibition or silencing reduced endothelial oxidative stress levels in aging vasculature and senescent endothelial cells. Moreover, DPP4 inhibition or knockdown normalized the expression and phosphorylation of AMP-activated protein kinase-α (AMPKα) and sirtuin 1 (SIRT1) expression. Furthermore, the beneficial effects of DPP4 inhibition or knockdown on endothelial cell senescence were at least partly dependent on SIRT1 and Nrf2 activation. In conclusion, our study demonstrated that DPP4 inhibition or silencing ameliorated endothelial senescence both in vivo and in vitro by regulating AMPK/SIRT1/Nrf2. DPP4 may be a new therapeutic target to combat endothelial senescence.
二肽基肽酶-4（DPP4）在许多心血管病理过程中升高，DPP4 抑制与炎症和氧化应激减少有关。本研究旨在研究 DPP4 在血管内皮细胞衰老中的作用。24 月龄的 Sprague-Dawley 大鼠通过饮用水给予 DPP4 抑制剂沙格列汀（10mg·kg·d），共 12 周。测量体重、心率、血糖和血压，并进行血管组织学实验。体外研究采用 HO 诱导的人脐静脉内皮细胞衰老模型进行。体内和体外研究均证实衰老血管内皮细胞中 DPP4 的升高，抑制或敲低 DPP4 可改善内皮细胞衰老。此外，DPP4 抑制或敲低可降低衰老血管和衰老内皮细胞中的内皮氧化应激水平。此外，DPP4 抑制或敲低可使 AMP 激活蛋白激酶-α（AMPKα）和沉默调节蛋白 1（SIRT1）的表达和磷酸化恢复正常。此外，DPP4 抑制或敲低对内皮细胞衰老的有益作用至少部分依赖于 SIRT1 和 Nrf2 的激活。总之，本研究表明，DPP4 抑制或敲低通过调节 AMPK/SIRT1/Nrf2 可改善体内和体外的内皮细胞衰老。DPP4 可能是对抗内皮细胞衰老的新治疗靶点。
