title: A novel mechanism of diabetic vascular endothelial dysfunction: Hypoadiponectinemia-induced NLRP3 inflammasome activation.
abstract: It has been well documented that hypoadiponectinemia is associated with impaired endothelium-dependent vasodilation. However, the exact molecular mechanism which mediates this process has not been fully described. The current study aimed to investigate the role of hypoadiponectinemia-induced NLRP3 inflammasome activation in diabetic vascular endothelial dysfunction and its molecular mechanism. Male adult adiponectin knockout mice and wild type mice were fed with a high fat diet to establish a type 2 diabetic mellitus model. In addition, human umbilical vein endothelial cells (HUVECs) were cultured and subjected to high glucose/high fat (HG/HF). The NLRP3 inflammasome activation was increased in type 2 diabetic mice and treatment of diabetic aortic segments with MCC950, a potent selective inhibitor of NLRP3 inflammasome ex vivo improved endothelial-dependent vasorelaxation. NLRP3 inflammasome activation and vascular endothelial injury were significantly increased in APN-KO mice compared with WT mice in diabetes and MCC950 decreased diabetic vascular endothelial dysfunction to comparable levels in APN-KO mice and WT mice. Adiponectin could decrease NLRP3 inflammasome activation and attenuate endothelial cell injury, which was abolished by NLRP3 inflammasome overexpression. Inhibition of peroxynitrite formation preferentially attenuated NLRP3 inflammasome activation in APN-KO diabetic mice. The current study demonstrated for the first time that hypoadiponectinemia-induced NLRP3 inflammasome activation was a novel mechanism of diabetic vascular endothelial dysfunction.
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Jinglong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Linying
authors.initials: L
authors.lastname: Xia
authors.affiliation: Department of Hepatic Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Fen
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Air Force General Hospital of People's Liberation Army, Beijing 100142, China.
authors.forename: Di
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Department of Cardiology, The Rocket Force General Hospital of People's Liberation Army, Beijing 100086, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Xin
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Helin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Fuyang
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xian
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Physiology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China; Department of Physiology, Fourth Military Medical University, Xi'an 710032, China. Electronic address: liuyimeishan@hotmail.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China. Electronic address: lingtao@fmmu.edu.cn.
authors.forename: Ling
authors.initials: L
authors.lastname: Tao
mesh_terms: D052242:Adiponectin / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D003925:Diabetic Angiopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008661:Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism*; D014664:Vasodilation / Q000235:genetics
chemical_list: D052242:Adiponectin; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse
keywords: Adiponectin; Endothelial cells; NLRP3 inflammasome; Oxidative/nitrative stress; Type 2 diabetic mellitus