title: Ampelopsin protects endothelial cells from hyperglycemia-induced oxidative damage by inducing autophagy via the AMPK signaling pathway.
abstract: Diabetic angiopathy is a major diabetes-specific complication that often begins with endothelial dysfunction induced by hyperglycemia; however, the pathological mechanisms of this progression remain unclear. Ampelopsin is a natural flavonol that has strong antioxidant activity, but little information is available regarding its antidiabetic effect. This study focused on the effect of ampelopsin on hyperglycemia-induced oxidative damage and the underlying mechanism of this effect in human umbilical vein endothelial cells (HUVECs). We found that hyperglycemia impaired autophagy in HUVECs through the inhibition of AMP-activated protein kinase (AMPK), which directly led to endothelial cell damage. Ampelopsin significantly attenuated the detrimental effect of hyperglycemia-induced cell dysfunction in a concentration-dependent manner in HUVECs. Ampelopsin significantly upregulated LC3-II, Beclin1, and Atg5 protein levels but downregulated p62 protein levels in HUVECs. Transmission electron microscopy and confocal microscopy indicated that ampelopsin notably induced autophagosomes and LC3-II dots, respectively. Additionally, the autophagy-specific inhibitor 3-MA, as well as Atg5 and Beclin1 siRNA pretreatment, markedly attenuated ampelopsin-induced autophagy, which subsequently abolished the protective effect of ampelopsin against hyperglycemia in HUVECs. Moreover, ampelopsin also increased AMPK activity and inhibited mTOR (mammalian target of rapamycin) complex activation. Ampelopsin-induced autophagy was attenuated by the AMPK antagonist compound C but strengthened by the AMPK agonist AICAR (5-minoimidazole-4-carboxamide ribonucleotide). Furthermore, AMPK siRNA transfection eliminated ampelopsin's alleviation of cell injury induced by hyperglycemia. The protective effect of ampelopsin against hyperglycemia-induced cell damage, which functions by targeting autophagy via AMPK activation, makes it a promising pharmacological treatment for type-2 diabetes.
authors.affiliation: Chongqing Key Laboratory of Nutrition and Food Safety, Research Center of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Liang
authors.affiliation: Chongqing Key Laboratory of Nutrition and Food Safety, Research Center of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Chongqing Key Laboratory of Nutrition and Food Safety, Research Center of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Linying
authors.initials: L
authors.lastname: Shi
authors.affiliation: Chongqing Key Laboratory of Nutrition and Food Safety, Research Center of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Chao
authors.initials: C
authors.lastname: Kang
authors.affiliation: Chongqing Key Laboratory of Nutrition and Food Safety, Research Center of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wan
authors.affiliation: Chongqing Key Laboratory of Nutrition and Food Safety, Research Center of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Chongqing Key Laboratory of Nutrition and Food Safety, Research Center of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Jundong
authors.initials: J
authors.lastname: Zhu
authors.forename: Mantian
authors.initials: M
authors.lastname: Mi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003925:Diabetic Angiopathies / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D005419:Flavonoids / Q000008:administration & dosage*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000975:Antioxidants; D005419:Flavonoids; C106407:ampelopsin; D055372:AMP-Activated Protein Kinases
keywords: AMPK; ampelopsin; autophagy; diabetes; endothelial cell