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Mitochondria‐targeted antioxidant therapy with MitoQ ameliorates age‐related vascular endothelial dysfunction
Author(s) -
GiosciaRyan Rachel Anna,
LaRocca Thomas J,
Zigler Melanie C,
Murphy Michael P,
Seals Douglas R
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1125.10
Subject(s) - oxidative stress , reactive oxygen species , nitrotyrosine , endothelial dysfunction , mitochondrion , medicine , mitochondrial ros , pharmacology , superoxide dismutase , chemistry , endocrinology , biochemistry , nitric oxide , nitric oxide synthase
Age‐related vascular endothelial dysfunction, characterized by a decline in endothelium‐dependent dilation (EDD), is mediated in large part by oxidative stress. Mitochondria are a major source of reactive oxygen species (ROS) and may be an important therapeutic target for reducing age‐related oxidative stress. We tested the hypothesis that MitoQ, a mitochondria‐targeted antioxidant, would improve vascular function in aging. Old mice (O, 26–28 mo) had elevated aortic whole‐cell (WC, O: 4964±127 AU p<0.05 vs. young [Y, 6–8 mo]: 1515±281) and mitochondria‐specific (MtS, O: 1370±170 p<0.05 vs. Y: 395±50) superoxide production (EPR), as well as ~2× greater (vs. Y) levels (Western blot) of nitrotyrosine (NT), a marker of oxidative protein modification. The age‐related increase in oxidative stress was associated with impaired maximal carotid artery EDD to acetylcholine (Ach; O: 67±8% p<0.05 vs. Y: 86±7%). Mitochondrial stress (0.5uM rotenone incubation) exacerbated endothelial dysfunction in arteries of O mice (~25% reduction in EDD, p<.05 vs. Ach alone), but not Y. MitoQ (250 uM in drinking water, 4 weeks) treatment in O mice (OMQ) normalized superoxide production (OMQ: WC, 1198±14; MtS, 658±112, both p<.05 vs. O) and NT. MitoQ treatment also restored EDD (OMQ: 92±4%, p<.05 vs. O) and conferred protection against acute mitochondrial stress (rotenone). Finally, ex‐vivo treatment of arteries with MitoQ abolished age‐related impairments in EDD. MitoQ may be a novel therapy for age‐related vascular dysfunction by reducing mitochondria‐derived oxidative stress. NIH AG000279 , AG039210 , AG013038