title: Mitochondria-targeted antioxidant (MitoQ) ameliorates age-related arterial endothelial dysfunction in mice.
abstract: Age-related arterial endothelial dysfunction, a key antecedent of the development of cardiovascular disease (CVD), is largely caused by a reduction in nitric oxide (NO) bioavailability as a consequence of oxidative stress. Mitochondria are a major source and target of vascular oxidative stress when dysregulated. Mitochondrial dysregulation is associated with primary ageing, but its role in age-related endothelial dysfunction is unknown. Our aim was to determine the efficacy of a mitochondria-targeted antioxidant, MitoQ, in ameliorating vascular endothelial dysfunction in old mice. Ex vivo carotid artery endothelium-dependent dilation (EDD) to increasing doses of acetylcholine was impaired by ∼30% in old (∼27 months) compared with young (∼8 months) mice as a result of reduced NO bioavailability (P < 0.05). Acute (ex vivo) and chronic (4 weeks in drinking water) administration of MitoQ completely restored EDD in older mice by improving NO bioavailability. There were no effects of age or MitoQ on endothelium-independent dilation to sodium nitroprusside. The improvements in endothelial function with MitoQ supplementation were associated with the normalization of age-related increases in total and mitochondria-derived arterial superoxide production and oxidative stress (nitrotyrosine abundance), as well as with increases in markers of vascular mitochondrial health, including antioxidant status. MitoQ also reversed the age-related increase in endothelial susceptibility to acute mitochondrial damage (rotenone-induced impairment in EDD). Our results suggest that mitochondria-derived oxidative stress is an important mechanism underlying the development of endothelial dysfunction in primary ageing. Mitochondria-targeted antioxidants such as MitoQ represent a promising novel strategy for the preservation of vascular endothelial function with advancing age and the prevention of age-related CVD.
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Gioscia-Ryan
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: LaRocca
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Sindler
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA.
authors.forename: Melanie C
authors.initials: MC
authors.lastname: Zigler
authors.affiliation: MRC Mitochondrial Biology Unit, Cambridge, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA seals@colorado.edu.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Seals
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D014652:Vascular Diseases / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000975:Antioxidants; D009943:Organophosphorus Compounds; D013481:Superoxides; D014451:Ubiquinone; D009569:Nitric Oxide; C429014:mitoquinone; D019001:Nitric Oxide Synthase