Mitochondria-targeted antioxidant (MitoQ) ameliorates age-related arterial endothelial dysfunction in mice.

TitleMitochondria-targeted antioxidant (MitoQ) ameliorates age-related arterial endothelial dysfunction in mice.
Publication TypeJournal Article
Year of Publication2014
AuthorsGioscia-Ryan, RA, LaRocca, TJ, Sindler, AL, Zigler, MC, Murphy, MP, Seals, DR
JournalJ Physiol
Volume592
Issue12
Pagination2549-61
Date Published2014 Jun 15
ISSN1469-7793
KeywordsAging, Animals, Antioxidants, Aorta, Thoracic, Endothelium, Vascular, Male, Mice, Inbred C57BL, Mitochondria, Nitric Oxide, Nitric Oxide Synthase, Organophosphorus Compounds, Oxidative Stress, Superoxides, Ubiquinone, Vascular Diseases, Vasodilation
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.

DOI10.1113/jphysiol.2013.268680
Alternate JournalJ. Physiol. (Lond.)
Citation Key10.1113/jphysiol.2013.268680
PubMed ID24665093
PubMed Central IDPMC4080937
Grant ListAG013038 / AG / NIA NIH HHS / United States
AG039210 / AG / NIA NIH HHS / United States
F31 AG047784 / AG / NIA NIH HHS / United States
MC_U105663142 / / Medical Research Council / United Kingdom
AG000279 / AG / NIA NIH HHS / United States
T32 AG000279 / AG / NIA NIH HHS / United States