title: Adverse alterations in mitochondrial function contribute to type 2 diabetes mellitus-related endothelial dysfunction in humans.
abstract: OBJECTIVE
  Mitochondrial dysfunction plays a key pathophysiological role in type 2 diabetes mellitus (T2DM). Data delineating relationships between mitochondrial and endothelial dysfunction in humans with T2DM are lacking.
  
  
  RESULTS
  In 122 human subjects (60 with T2DM, 62 without T2DM), we measured endothelial function by brachial artery ultrasound (flow mediated dilation) and digital pulse amplitude tonometery. Endothelial function in arterioles isolated from gluteal subcutaneous adipose was measured by videomicroscopy. In arterioles and mononuclear cells, we measured inner mitochondrial membrane potential (Δψ(m)), mitochondrial mass, and mitochondrial superoxide production using fluorophores. Endothelial function was impaired in T2DM subjects versus control subjects. Δψ(m) magnitude was larger and mitochondrial mass was lower in arterioles and mononuclear cells in T2DM. Mononuclear mitochondrial mass correlated with flow-mediated dilation and pulse amplitude tonometery (ρ=0.38 and 0.33, P=0.001 and 0.02, respectively), and mononuclear mitochondrial superoxide production inversely correlated with flow-mediated dilation (ρ=-0.58, P=0.03). Low doses of 2 different mitochondrial uncoupling agents (carbonyl cyanide m-chlorophenyl hydrazone and 2,4-dinitrophenol) that reduce Δψ(m) magnitude and a mitochondrial-targeted antioxidant (MitoTEMPOL) improved endothelial function and reduced mitochondrial superoxide levels in T2DM arterioles.
  
  
  CONCLUSIONS
  Mitochondrial dysfunction may play a central role in the impairment of endothelial dysfunction in T2DM.
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Tinoy J
authors.initials: TJ
authors.lastname: Kizhakekuttu
authors.forename: Jingli
authors.initials: J
authors.lastname: Wang
authors.forename: Kodlipet
authors.initials: K
authors.lastname: Dharmashankar
authors.forename: Rong
authors.initials: R
authors.lastname: Ying
authors.forename: David D
authors.initials: DD
authors.lastname: Gutterman
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Vita
authors.forename: Michael E
authors.initials: ME
authors.lastname: Widlansky
mesh_terms: D019297:2,4-Dinitrophenol / Q000494:pharmacology; D000328:Adult; D001160:Arterioles / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology; D001916:Brachial Artery / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology*; D005260:Female; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology*; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D063177:Pulse Wave Analysis; D013481:Superoxides / Q000378:metabolism*; D014463:Ultrasonography; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: C555916:MitoTEMPO; D009943:Organophosphorus Compounds; D010880:Piperidines; D014475:Uncoupling Agents; D013481:Superoxides; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D019297:2,4-Dinitrophenol