Wang Huanyuan, Zhou Yi, Guo Zhiying, Dong Yu, Xu Jiahui, Huang Haixia, Liu Huirong, Wang Wen
1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
2 Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Diseases, Beijing, China.
J Cardiovasc Pharmacol Ther. 2018 Jan;23(1):66-78. doi: 10.1177/1074248417715001. Epub 2017 Jun 15.
Although the contributions of sitagliptin to endothelial function in diabetes mellitus were previously reported, the potential mechanisms still remain undefined. Our research was intended to explore the underlying mechanisms of protective effects of sitagliptin treatment on endothelial dysfunction in Zucker diabetic fatty (ZDF) rats. Male lean nondiabetic Zucker rats were used as control and male obese ZDF rats were randomly divided into ZDF and ZDF + sitagliptin groups. The significant decrease in endothelium-dependent relaxation induced by acetylcholine was observed in mesenteric arteries and thoracic aorta rings of ZDF rats. The administration of sitagliptin restored the vascular function effectively. The morphology study showed severe endothelial injuries in thoracic aortas of ZDF rats, and sitagliptin treatment attenuated these changes. The increased malondialdehyde levels and decreased superoxide dismutase activities in serum of ZDF rats were reversed by sitagliptin treatment. Sitagliptin also increased the expression of endothelial nitric oxide synthase and microtubule-associated protein 1 light chain 3 (LC3) and decreased the expression of inducible nitric oxide synthase, 3-nitrotyrosine, and p62 in ZDF rats. After giving Fe (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride porphyrin pentachloride (FeTMPyP, a peroxynitrite [ONOO] scavenger) or sitagliptin to high-glucose (30 mmol/L, 48 hours) cultured human umbilical vein endothelial cells (HUVECs), the increased levels of Beclin-1 and lysosome-associated membrane protein type 2 were detected. Both FeTMPyP and sitagliptin also significantly increased the number of mRFP-GFP-LC3 dots per cell, suggesting that autophagic flux was increased in HUVECs. Our study indicated that sitagliptin treatment can improve the endothelium-dependent relaxation and attenuate the endothelial impairment of ZDF rats. The protective effects of sitagliptin are possibly related to antiperoxynitrite and promoting autophagy.
尽管先前已有关于西他列汀对糖尿病患者内皮功能影响的报道，但其潜在机制仍不明确。我们的研究旨在探索西他列汀治疗对Zucker糖尿病脂肪（ZDF）大鼠内皮功能障碍保护作用的潜在机制。雄性瘦型非糖尿病Zucker大鼠作为对照，雄性肥胖ZDF大鼠随机分为ZDF组和ZDF + 西他列汀组。在ZDF大鼠的肠系膜动脉和胸主动脉环中观察到乙酰胆碱诱导的内皮依赖性舒张显著降低。给予西他列汀有效恢复了血管功能。形态学研究显示ZDF大鼠胸主动脉存在严重的内皮损伤，而西他列汀治疗减轻了这些变化。西他列汀治疗逆转了ZDF大鼠血清中丙二醛水平升高和超氧化物歧化酶活性降低的情况。西他列汀还增加了ZDF大鼠内皮型一氧化氮合酶和微管相关蛋白1轻链3（LC3）的表达，并降低了诱导型一氧化氮合酶、3-硝基酪氨酸和p62的表达。给高糖（30 mmol/L，48小时）培养的人脐静脉内皮细胞（HUVECs）给予四（1-甲基-4-吡啶基）卟啉五氯化铁（FeTMPyP，一种过氧亚硝酸盐[ONOO]清除剂）或西他列汀后，检测到Beclin-1和溶酶体相关膜蛋白2型水平升高。FeTMPyP和西他列汀均显著增加了每个细胞中mRFP-GFP-LC3斑点的数量，表明HUVECs中的自噬通量增加。我们的研究表明，西他列汀治疗可改善ZDF大鼠的内皮依赖性舒张并减轻内皮损伤。西他列汀的保护作用可能与抗过氧亚硝酸盐和促进自噬有关。
