title: Glutathione administration reduces mitochondrial damage and shifts cell death from necrosis to apoptosis in ageing diabetic mice hearts during exercise.
abstract: OBJECTIVE
  The effect of antioxidants on ageing type 2 diabetic (T2D) hearts during exercise is unclear. We hypothesized that GSH therapy during exercise reduces mitochondrial oxidative stress (mOXS) and cell death in ageing db/db mice hearts.
  
  
  METHODS
  The effect of GSH on cardiac mOXS and cell death was evaluated both in vivo and in vitro.
  
  
  RESULTS
  During exercise, GSH treatment protected db/db hearts from exaggerated mOXS without reducing total cell death. Despite similar cell death, investigations on apoptosis-specific single-stranded DNA breaks and necrosis-specific damage provided the first in vivo evidence of a shift from necrosis to apoptosis, with reduced fibrosis following GSH administration in exercised db/db hearts. Further support for a GSH-regulated 'switch' in death phenotypes came from NIH-3T3 fibroblasts and H9c2 cardiomyocytes treated with H2 O2 , a reactive oxygen species (ROS). Similar to in vivo findings, augmenting GSH by overexpressing glutamyl cysteine ligase (GCLc) protected fibroblasts and cardiomyocytes from necrosis induced by H2 O2 , but elevated caspase-3 and apoptosis instead. Similar to in vivo findings, where GSH therapy in normoglycaemic mice suppressed endogenous antioxidants and augmented caspase-3 activity, GCLc overexpression during staurosporine-induced death, which was not characterized by ROS, increased GSH efflux and aggravated death in fibroblasts and cardiomyocytes, confirming that oxidative stress is required for GSH-mediated cytoprotection.
  
  
  CONCLUSIONS
  While GSH treatment is useful for reducing mOXS and attenuating necrosis and fibrosis in ageing T2D hearts during exercise, such antioxidant treatment could be counterproductive in the healthy heart during exercise.
authors.affiliation: Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Golbidi
authors.forename: A
authors.initials: A
authors.lastname: Botta
authors.forename: S
authors.initials: S
authors.lastname: Gottfred
authors.forename: A
authors.initials: A
authors.lastname: Nusrat
authors.forename: I
authors.initials: I
authors.lastname: Laher
authors.forename: S
authors.initials: S
authors.lastname: Ghosh
mesh_terms: D016475:3T3 Cells; D000375:Aging / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004249:DNA Damage; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005355:Fibrosis; D005978:Glutathione / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D019803:Glutathione Disulfide / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009336:Necrosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010805:Physical Conditioning, Animal / Q000502:physiology*; D051381:Rats
chemical_list: D002316:Cardiotonic Agents; D020169:Caspases; D005978:Glutathione; D019803:Glutathione Disulfide