title: The SGLT-2 Inhibitor Dapagliflozin Has a Therapeutic Effect on Atherosclerosis in Diabetic ApoE-/-Mice.
abstract: Background. Our study aimed to observe the effect of sodium glucose cotransporter-2 (SGLT2) inhibitor dapagliflozin on diabetic atherosclerosis and investigate the subsequent mechanism.Methods. Aortic atherosclerosis was induced in streptozotocin induced diabetic ApoE-/-mice by feeding with high-fat diet, and dapagliflozin was administrated intragastrically for 12 weeks as treatment. Effects of dapagliflozin on indices of glucose and fat metabolism, IL-1β, IL-18, NLRP3 protein levels, and the reactive oxygen species (ROS) were measured. The atherosclerosis was evaluated by oil red O and hematoxylin-eosin staining. The effects of dapagliflozin on the IL-1βproduction in culturing primary macrophages of wild type and NLRP3-/-knockout mice were investigated for mechanism analyses.Results. Dapagliflozin treatment showed favorable effects on glucose and fat metabolism, partially reversed the formation of atherosclerosis, inhibited macrophage infiltration, and enhanced the stability of lesion. Also, reduced production of IL-1β, IL-18, NLRP3 protein, and mitochondrial ROS in the aortic tissues was detected with dapagliflozin treatment. In vitro, NLRP3 inflammasome was activated by hyperglucose and hyperlipid through ROS pathway.Conclusions. Dapagliflozin may be of therapeutic potential for diabetic atherosclerosis induced by high-fat diet, and these benefits may depend on the inhibitory effect on the secretion of IL-1βby macrophages via the ROS-NLRP3-caspase-1 pathway.
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Third Military Medical University, Chongqing 400038, China.
authors.forename: Weiling
authors.identifier: 0000-0001-9375-9726
authors.initials: W
authors.lastname: Leng
authors.affiliation: Department of Internal Medicine, Section of Digestive Diseases, Yale University of Medicine, New Haven, CT 06520, USA.
authors.forename: Xinshou
authors.identifier: 0000-0003-3423-0042
authors.initials: X
authors.lastname: Ouyang
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Third Military Medical University, Chongqing 400038, China.
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Lei
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Third Military Medical University, Chongqing 400038, China.
authors.forename: Mingxia
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Third Military Medical University, Chongqing 400038, China.
authors.forename: Liu
authors.identifier: 0000-0003-0966-2804
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Third Military Medical University, Chongqing 400038, China.
authors.forename: Qinan
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Third Military Medical University, Chongqing 400038, China.
authors.forename: Wuquan
authors.initials: W
authors.lastname: Deng
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Third Military Medical University, Chongqing 400038, China.
authors.forename: Ziwen
authors.identifier: 0000-0001-6909-2538
authors.initials: Z
authors.lastname: Liang
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000150:complications / Q000188:drug therapy*; D001559:Benzhydryl Compounds / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism; D048909:Diabetes Complications / Q000188:drug therapy*; D003921:Diabetes Mellitus, Experimental; D005947:Glucose / Q000378:metabolism; D005960:Glucosides / Q000627:therapeutic use*; D058847:Inflammasomes / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D001057:Apolipoproteins E; D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; C490299:Slc5a2 protein, mouse; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C529054:dapagliflozin; D005947:Glucose