title: SIRT3 Deficiency Induces Endothelial Insulin Resistance and Blunts Endothelial-Dependent Vasorelaxation in Mice and Human with Obesity.
abstract: Recent evidence implicates the critical role of Sirtuin 3 (SIRT3) in the development of many metabolic diseases, but the contribution of SIRT3 to vascular homeostasis remains largely unknown. The aim of this study was to investigate the role of SIRT3 in endothelial insulin resistance and vascular dysfunction in obesity. We found an impaired insulin-induced mesenteric vasorelaxation and concomitant reduced vascular SIRT3 expression in morbid obese human subjects compared with the non-obese subjects. Downregulation of SIRT3 in cultured human endothelial cells increased mitochondrial reactive oxygen species (mtROS) and impaired insulin signaling as evidenced by decreased phosphorylation of Akt and endothelial nitric oxide synthase and subsequent reduced nitric oxide (NO) release. In addition, obese mice induced by 24-week high-fat diet (HFD) displayed an impaired endothelium-dependent vasorelaxation to both insulin and acetylcholine, which was further exacerbated by the gene deletion of Sirt3. Scavenging of mtROS not only restored insulin-stimulated NO production in SIRT3 knockdown cells, but also improved insulin-induced vasorelaxation in SIRT3 knockout mice fed with HFD. Taken together, our findings suggest that SIRT3 positively regulates endothelial insulin sensitivity and show that SIRT3 deficiency and resultant increased mtROS contribute to vascular dysfunction in obesity.
authors.affiliation: Department of Aerospace Medicine, Fourth Military Medical University, 169 Changlexi Road, Xi'an 710032, China.|Department of Physiology, Fourth Military Medical University, 169 Changlexi Road, Xi'an 710032, China.|Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 169 Changlexi Road, Xi'an 710032, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Aerospace Medicine, Fourth Military Medical University, 169 Changlexi Road, Xi'an 710032, China.
authors.forename: Julei
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Aerospace Medicine, Fourth Military Medical University, 169 Changlexi Road, Xi'an 710032, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Xing
authors.affiliation: Department of Aerospace Medicine, Fourth Military Medical University, 169 Changlexi Road, Xi'an 710032, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Aerospace Medicine, Fourth Military Medical University, 169 Changlexi Road, Xi'an 710032, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Aerospace Medicine, Fourth Military Medical University, 169 Changlexi Road, Xi'an 710032, China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Aerospace Medicine, Fourth Military Medical University, 169 Changlexi Road, Xi'an 710032, China.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Aerospace Medicine, Fourth Military Medical University, 169 Changlexi Road, Xi'an 710032, China.
authors.forename: Xiaona
authors.initials: X
authors.lastname: Ning
authors.affiliation: Department of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, 169 Changlexi Road, Xi'an 710032, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Ji
authors.affiliation: Department of Aerospace Medicine, Fourth Military Medical University, 169 Changlexi Road, Xi'an 710032, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, 169 Changlexi Road, Xi'an 710032, China.
authors.forename: Qingchuan
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Department of Aerospace Medicine, Fourth Military Medical University, 169 Changlexi Road, Xi'an 710032, China.|Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 169 Changlexi Road, Xi'an 710032, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
mesh_terms: D000818:Animals; D004730:Endothelium, Vascular / Q000166:cytology*; D006801:Humans; D007333:Insulin Resistance; D051379:Mice; D009765:Obesity / Q000503:physiopathology*; D056566:Sirtuin 3 / Q000235:genetics*; D014664:Vasodilation
chemical_list: C525046:Sirt3 protein, mouse; D056566:Sirtuin 3