title: Altered mitochondrial dynamics contributes to endothelial dysfunction in diabetes mellitus.
abstract: BACKGROUND
  Endothelial dysfunction contributes to the development of atherosclerosis in patients with diabetes mellitus, but the mechanisms of endothelial dysfunction in this setting are incompletely understood. Recent studies have shown altered mitochondrial dynamics in diabetes mellitus with increased mitochondrial fission and production of reactive oxygen species. We investigated the contribution of altered dynamics to endothelial dysfunction in diabetes mellitus.
  
  
  RESULTS
  We observed mitochondrial fragmentation (P=0.002) and increased expression of fission-1 protein (Fis1; P<0.0001) in venous endothelial cells freshly isolated from patients with diabetes mellitus (n=10) compared with healthy control subjects (n=9). In cultured human aortic endothelial cells exposed to 30 mmol/L glucose, we observed a similar loss of mitochondrial networks and increased expression of Fis1 and dynamin-related protein-1 (Drp1), proteins required for mitochondrial fission. Altered mitochondrial dynamics was associated with increased mitochondrial reactive oxygen species production and a marked impairment of agonist-stimulated activation of endothelial nitric oxide synthase and cGMP production. Silencing Fis1 or Drp1 expression with siRNA blunted high glucose-induced alterations in mitochondrial networks, reactive oxygen species production, endothelial nitric oxide synthase activation, and cGMP production. An intracellular reactive oxygen species scavenger provided no additional benefit, suggesting that increased mitochondrial fission may impair endothelial function via increased reactive oxygen species.
  
  
  CONCLUSIONS
  These findings implicate increased mitochondrial fission as a contributing mechanism for endothelial dysfunction in diabetic states.
authors: Boston University School of Medicine, 88 East Newton Street, Boston, MA 02118., USA.
authors: Sherene M
authors: SM
authors: Shenouda
authors: Michael E
authors: ME
authors: Widlansky
authors: Kai
authors: K
authors: Chen
authors: Guoquan
authors: G
authors: Xu
authors: Monika
authors: M
authors: Holbrook
authors: Corey E
authors: CE
authors: Tabit
authors: Naomi M
authors: NM
authors: Hamburg
authors: Alissa A
authors: AA
authors: Frame
authors: Tara L
authors: TL
authors: Caiano
authors: Matthew A
authors: MA
authors: Kluge
authors: Mai-Ann
authors: MA
authors: Duess
authors: Aaron
authors: A
authors: Levit
authors: Brian
authors: B
authors: Kim
authors: Mor-Li
authors: ML
authors: Hartman
authors: Lija
authors: L
authors: Joseph
authors: Orian S
authors: OS
authors: Shirihai
authors: Joseph A
authors: JA
authors: Vita
mesh_terms: D000328:Adult; D001011:Aorta / Q000378:metabolism; D015992:Body Mass Index; D002460:Cell Line; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000096:biosynthesis; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology*; D034281:Dynamins; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D016166:Free Radical Scavengers / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000096:biosynthesis; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C476525:FIS1 protein, human; D016166:Free Radical Scavengers; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D052250:Nitric Oxide Synthase Type III; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins; D006152:Cyclic GMP; D005947:Glucose