Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 592 (12), 2549-61

Mitochondria-targeted Antioxidant (MitoQ) Ameliorates Age-Related Arterial Endothelial Dysfunction in Mice

Affiliations

Mitochondria-targeted Antioxidant (MitoQ) Ameliorates Age-Related Arterial Endothelial Dysfunction in Mice

Rachel A Gioscia-Ryan et al. J Physiol.

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.

Figures

Figure 1
Figure 1. MitoQ reverses the age-related decline in endothelium-dependent dilation
Endothelium-dependent dilation (EDD) dose responses to acetylcholine (ACh) in carotid arteries. A, primary group comparisons of young (YC) and old (OC) control mice provided with normal drinking water and old mice supplemented with MitoQ (OMQ). B, control group comparisons of young (YMP) and old (OMP) mice treated with decyl-triphenylphosphonium (TPP) and young mice supplemented with MitoQ (YMQ) (*P < 0.05 vs. YC; main effect of group). C, maximal EDD to ACh (*P < 0.05 vs. YC). D, endothelium-independent dilation to the nitric oxide donor sodium nitroprusside. Data are presented on a percentage basis to account for differences in vessel diameter among groups. Values are means ± s.e.m. (n = 6–13/group).
Figure 2
Figure 2. MitoQ restores nitric oxide-dependent endothelium-dependent dilation in old mice
A, endothelium-dependent dilation (EDD) dose responses to acetylcholine (ACh) in the absence/presence of the nitric oxide (NO) inhibitor N-nitro-l-arginine methyl ester (l-NAME) in carotid arteries of young (YC) and old (OC) control mice and young (YMQ) and old (OMQ) MitoQ-supplemented mice. Data are presented on a percentage basis to account for differences in vessel diameter among groups. (*P < 0.05 vs. YC, main effect of group for dose response to ACh alone; #P < 0.05 within-group, dose response to Ach + l-NAME vs. dose response to ACh alone.) There were no group differences in the dose response to ACh + l-NAME. B, NO-dependent dilation (maxEDDACh–maxEDDACh+l-NAME) (*P < 0.05 vs. YC). C, total NOS activity in the aorta (*P < 0.05 vs. YC). All data are presented as means ± s.e.m. (n = 6–8/group).
Figure 3
Figure 3. MitoQ normalizes vascular oxidative stress in old mice
A, nitrotyrosine (NT), a biomarker of oxidative protein damage, in arteries (aorta) of young (YC) and old (OC) control mice and young (YMQ) and old (OMQ) MitoQ-supplemented mice; representative Western blot images (25 kDa and 55 kDa bands) are shown below. B, whole-cell superoxide production in aortic segments; representative electron paramagnetic resonance spectra are shown below. Protein expression data are normalized to GAPDH expression. All data are normalized to YC mean values and presented as means ± s.e.m. (n = 5–8/group; *P < 0.05 vs. YC).
Figure 4
Figure 4. MitoQ reduces arterial mitochondria-derived oxidative stress and suppression of function in old mice
A, mitochondria-specific superoxide production in aortic segments of young (YC) and old (OC) control mice and young (YMQ) and old (OMQ) MitoQ-supplemented mice; representative electron paramagnetic resonance spectra are shown below. B, aortic protein expression of phosphorylated (serine36) p66SHC; representative Western blot images are shown below. C, dose response and maximal (inset) endothelium-dependent dilation to acetylcholine in the presence of MitoQ (1.0 μm, 40 min incubation to scavenge mitochondrial reactive oxygen species). Protein expression data are normalized to GAPDH expression. Protein expression and mitochondrial superoxide data are normalized to YC mean values. All values are presented as means ± s.e.m. (n = 6–8/group; *P < 0.05 vs. YC).
Figure 5
Figure 5. MitoQ improves markers of mitochondrial health in old mice
Protein expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) (A), manganese superoxide dismutase (MnSOD) (B) and cytochrome c oxidase subunit IV (COX IV) (C) in aorta of young (YC) and old (OC) control mice and young (YMQ) and old (OMQ) MitoQ-supplemented mice; representative Western blot images are shown below. Protein expression data are normalized to GAPDH expression and YC mean values and presented as means ± s.e.m. (n = 6–10/group; *P < 0.05 vs. YC).
Figure 6
Figure 6. MitoQ improves resistance to acute mtROS stress in arteries of old mice
Endothelium-dependent dilation (EDD) dose responses to acetylcholine (ACh) in the absence/presence of rotenone (0.5 μl, 40 min incubation to induce mitochondrial superoxide production) in carotid arteries of young control (YC) and MitoQ-supplemented (YMQ) mice (A) and old control (OC) and MitoQ-supplemented (OMQ) mice (B) (n = 5–6/group). Data are presented on a percentage basis to account for differences in vessel diameter among groups. Data for young and old mice are presented separately for clarity. [*P < 0.05 within-group, dose response to Ach + rotenone vs. dose response to ACh alone; #P < 0.05 vs. OMQ (main effect of group) for dose response to ACh alone.] C, impairment in EDD induced by acute incubation with rotenone (maxEDDACh–maxEDDACh+ROTENONE). Data are presented as means ± s.e.m. (n = 5–6/group; *P < 0.05 vs. within-group maximal dilation to ACh alone).
Figure 7
Figure 7. Working hypothesis
An increase in vascular mitochondria-derived reactive oxygen species (mtROS) production and associated dysregulation of mitochondrial homeostasis with primary ageing contributes to a state of oxidative stress and a reduction in nitric oxide (NO) bioavailability, which promote the development of endothelial dysfunction. Mitochondria-targeted antioxidant treatment with MitoQ may be a promising therapeutic strategy for reducing vascular mitochondrial oxidative stress, restoring vascular mitochondrial homeostasis, and preserving endothelial function in advancing age to reduce cardiovascular disease (CVD) risk.

Similar articles

See all similar articles

Cited by 53 articles

See all "Cited by" articles

Publication types

MeSH terms

Feedback