title: Resolution of mitochondrial oxidant stress improves aged-cardiovascular performance.
abstract: BACKGROUND
  Senescence is a major factor that increases oxidative stress in mitochondria, which contributes toward the pathogenesis of heart disease. However, the effect of antioxidant therapy on cardiac mitochondria in aged-cardiac performance remains elusive.
  
  
  OBJECTIVE
  We postulated that the mitochondrial targeting of superoxide scavenging would have benefits in the aged heart.
  
  
  RESULTS
  Generation of superoxide in the mitochondria and nicotinamide adenine dinucleotide phosphate oxidase activity increased in the heart of old mice compared with that in young mice. In old mice treated with a mitochondria-targeted antioxidant MitoTEMPO (180 µg/kg/day, 28 days) co-infusion using a subcutaneously implanted minipump, levels of superoxide in the mitochondria and nicotinamide adenine dinucleotide phosphate oxidase activity as well as hydrogen peroxide decreased markedly in cardiomyocytes. Treatment with MitoTEMPO in old mice improved the systolic and diastolic function assessed by echocardiography. Endothelium-dependent vasodilation in isolated coronary arteries and endothelial nitric-oxide synthase phosphorylation were impaired in old mice compared with that in young mice and were improved by MitoTEMPO treatment. Mitochondria from the old mice myocardium showed lower rates of complex I-dependent and II-dependent respiration compared with that from young mice. Supplementation of MitoTEMPO in old mice improved the respiration rates and efficiency of ATP generation in mitochondria to a level similar to that of young mice.
  
  
  CONCLUSIONS
  Resolution of oxidative stress in mitochondria by MitoTEMPO in old mice restored cardiac function and the capacity of coronary vasodilation to the same magnitude observed in young mice. An antioxidant strategy targeting mitochondria could have a therapeutic benefit in heart disease with senescence.
authors.affiliation: Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Owada
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamauchi
authors.forename: Shu-Ichi
authors.initials: SI
authors.lastname: Saitoh
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Miura
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Machii
authors.forename: Yasuchika
authors.initials: Y
authors.lastname: Takeishi
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000367:Age Factors; D000375:Aging / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology*; D019069:Cell Respiration / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D055104:Infusions, Subcutaneous; D008297:Male; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000975:Antioxidants; C555916:MitoTEMPO; D009943:Organophosphorus Compounds; D010880:Piperidines; D013481:Superoxides; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D019255:NADPH Oxidases