title: Resolution of mitochondrial oxidative stress rescues coronary collateral growth in Zucker obese fatty rats.
abstract: OBJECTIVE
  We have previously found abrogated ischemia-induced coronary collateral growth in Zucker obese fatty (ZOF) rats compared with Zucker lean (ZLN) rats. Because ZOF rats have structural abnormalities in their mitochondria suggesting dysfunction and also show increased production of O(2), we hypothesized that mitochondrial dysfunction caused by oxidative stress impairs coronary collateral growth in ZOF.
  
  
  RESULTS
  Increased levels of reactive oxygen species were observed in aortic endothelium and smooth muscle cells in ZOF rats compared with ZLN rats. Reactive oxygen species levels were decreased by the mitochondria-targeted antioxidants MitoQuinone (MQ) and MitoTempol (MT) as assessed by MitoSox Red and dihydroethidine staining. Lipid peroxides (a marker of oxidized lipids) were increased in ZOF by ≈47% compared with ZLN rats. The elevation in oxidative stress was accompanied by increased antioxidant enzymes, except glutathione peroxidase-1, and by increased uncoupling protein-2 in ZOF versus ZLN rats. In addition, elevated respiration rates were also observed in the obese compared with lean rats. Administration of MQ significantly normalized the metabolic profiles and reduced lipid peroxides in ZOF rats to the same level observed in lean rats. The protective effect of MQ also suppressed the induction of uncoupling protein-2 in the obese rats. Resolution of mitochondrial oxidative stress by MQ or MT restored coronary collateral growth to the same magnitude observed in ZLN rats in response to repetitive ischemia.
  
  
  CONCLUSIONS
  We conclude that mitochondrial oxidative stress and dysfunction play a key role in disrupting coronary collateral growth in obesity and the metabolic syndrome, and elimination of the mitochondrial oxidative stress with MQ or MT rescues collateral growth.
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
authors.forename: Yuh Fen
authors.initials: YF
authors.lastname: Pung
authors.forename: Petra
authors.initials: P
authors.lastname: Rocic
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.forename: Robin A J
authors.initials: RA
authors.lastname: Smith
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hafemeister
authors.forename: Vahagn
authors.initials: V
authors.lastname: Ohanyan
authors.forename: Giacinta
authors.initials: G
authors.lastname: Guarini
authors.forename: Liya
authors.initials: L
authors.lastname: Yin
authors.forename: William M
authors.initials: WM
authors.lastname: Chilian
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D003097:Collateral Circulation / Q000187:drug effects* / Q000502:physiology; D003331:Coronary Vessels / Q000187:drug effects / Q000254:growth & development*; D004195:Disease Models, Animal; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008054:Lipid Peroxides / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism* / Q000503:physiopathology; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000502:physiology; D024101:Mitochondrial Proteins / Q000378:metabolism; D009765:Obesity / Q000378:metabolism* / Q000503:physiopathology; D009943:Organophosphorus Compounds / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D017382:Reactive Oxygen Species / Q000378:metabolism; D014451:Ubiquinone / Q000494:pharmacology / Q000031:analogs & derivatives
chemical_list: D000975:Antioxidants; D008054:Lipid Peroxides; C555916:MitoTEMPO; D024101:Mitochondrial Proteins; D009943:Organophosphorus Compounds; D010880:Piperidines; D017382:Reactive Oxygen Species; D014451:Ubiquinone; C429014:mitoquinone