title: CR6-Interacting Factor 1 Deficiency Impairs Vascular Function by Inhibiting the Sirt1-Endothelial Nitric Oxide Synthase Pathway.
abstract: Mitochondrial dysfunction has emerged as a major contributing factor to endothelial dysfunction and vascular disease, but the key mechanisms underlying mitochondrial dysfunction-induced endothelial dysfunction remain to be elucidated. In this study, we aim at determining whether mitochondrial dysfunction in endothelial cells plays a key role in vascular disease, by examining the phenotype of endothelial-specific CR6-interacting factor 1 (CRIF1) knockout mice. We also used siRNA-mediated downregulation of CRIF1 gene in the endothelial cells to study about the in vitro pathophysiological underlying mechanisms.
  
  
  
  Downregulation of CRIF1 in endothelial cells caused disturbances of mitochondrial oxidative phosphorylation complexes and membrane potential, leading to enhanced mitochondrial reactive oxygen species production. Gene silencing of CRIF1 results in decreased SIRT1 expression along with increased endothelial nitric oxide synthase (eNOS) acetylation, leading to reduced nitric oxide production both in vitro and in vivo. Endothelium-dependent vasorelaxation of aortic rings from CRIF1 knockout (KO) mice was considerably less than in wild-type mice, and it was partially recovered by Sirt1 overexpression in CRIF1 KO mice.
  
  
  
  Our results show for the first time a relationship between mitochondrial dysfunction and impaired vascular function induced in CRIF1 deficiency conditions and also the possible underlying pathway involved.
  
  
  
  These findings indicate that CRIF1 plays an important role in maintaining mitochondrial and endothelial function through its effects on the SIRT1-eNOS pathway. Antioxid. Redox Signal. 27, 234-249.
authors.affiliation: 1 Department of Physiology, School of Medicine, Chungnam National University , Daejeon, Republic of Korea.|2 Department of Medical Science, School of Medicine, Chungnam National University , Daejeon, Republic of Korea.
authors.forename: Harsha
authors.initials: H
authors.lastname: Nagar
authors.affiliation: 3 Department of Endocrinology, School of Medicine, Chungnam National University , Daejeon, Republic of Korea.
authors.forename: Saet-Byel
authors.initials: SB
authors.lastname: Jung
authors.affiliation: 4 Department of Biochemistry, School of Medicine, Chungnam National University , Daejeon, Republic of Korea.
authors.forename: Min Jeong
authors.initials: MJ
authors.lastname: Ryu
authors.affiliation: 1 Department of Physiology, School of Medicine, Chungnam National University , Daejeon, Republic of Korea.|2 Department of Medical Science, School of Medicine, Chungnam National University , Daejeon, Republic of Korea.
authors.forename: Su-Jung
authors.initials: SJ
authors.lastname: Choi
authors.affiliation: 1 Department of Physiology, School of Medicine, Chungnam National University , Daejeon, Republic of Korea.|2 Department of Medical Science, School of Medicine, Chungnam National University , Daejeon, Republic of Korea.
authors.forename: Shuyu
authors.initials: S
authors.lastname: Piao
authors.affiliation: 5 Department of Neurology, Chungnam National University Hospital , Daejeon, Republic of Korea.
authors.forename: Hee-Jung
authors.initials: HJ
authors.lastname: Song
authors.affiliation: 6 Department of Thoracic and Cardiovascular Surgery, Chungnam National University Hospital , Daejeon, Republic of Korea.
authors.forename: Shin Kwang
authors.initials: SK
authors.lastname: Kang
authors.affiliation: 2 Department of Medical Science, School of Medicine, Chungnam National University , Daejeon, Republic of Korea.|7 Department of Anatomy, School of Medicine, Chungnam National University , Daejeon, Republic of Korea.
authors.forename: Nara
authors.initials: N
authors.lastname: Shin
authors.affiliation: 2 Department of Medical Science, School of Medicine, Chungnam National University , Daejeon, Republic of Korea.|7 Department of Anatomy, School of Medicine, Chungnam National University , Daejeon, Republic of Korea.
authors.forename: Dong Woon
authors.initials: DW
authors.lastname: Kim
authors.affiliation: 8 Division of Cardiology, Department of Medicine, Chungnam National University Hospital, Chungnam National University School of Medicine , Daejeon, Republic of Korea.
authors.forename: Seon-Ah
authors.initials: SA
authors.lastname: Jin
authors.affiliation: 8 Division of Cardiology, Department of Medicine, Chungnam National University Hospital, Chungnam National University School of Medicine , Daejeon, Republic of Korea.
authors.forename: Jin-Ok
authors.initials: JO
authors.lastname: Jeong
authors.affiliation: 9 Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine , Iowa City, Iowa.
authors.forename: Kaikobad
authors.initials: K
authors.lastname: Irani
authors.affiliation: 1 Department of Physiology, School of Medicine, Chungnam National University , Daejeon, Republic of Korea.|2 Department of Medical Science, School of Medicine, Chungnam National University , Daejeon, Republic of Korea.
authors.forename: Byeong Hwa
authors.initials: BH
authors.lastname: Jeon
authors.affiliation: 3 Department of Endocrinology, School of Medicine, Chungnam National University , Daejeon, Republic of Korea.
authors.forename: Minho
authors.initials: M
authors.lastname: Shong
authors.affiliation: 2 Department of Medical Science, School of Medicine, Chungnam National University , Daejeon, Republic of Korea.|4 Department of Biochemistry, School of Medicine, Chungnam National University , Daejeon, Republic of Korea.
authors.forename: Gi Ryang
authors.initials: GR
authors.lastname: Kweon
authors.affiliation: 1 Department of Physiology, School of Medicine, Chungnam National University , Daejeon, Republic of Korea.|2 Department of Medical Science, School of Medicine, Chungnam National University , Daejeon, Republic of Korea.
authors.forename: Cuk-Seong
authors.initials: CS
authors.lastname: Kim
mesh_terms: D000107:Acetylation; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D055786:Gene Knockout Techniques; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics*; D010085:Oxidative Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; C476586:GADD45GIP1 protein, human; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: CRIF1; OXPHOS complex; SIRT1; eNOS; mitochondrial dysfunction; nitric oxide