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

Abstract

Key pointsr The development of age-related arterial endothelial dysfunction, a key antecedent of increased cardiovascular disease (CVD) risk, is mediated largely by reduced nitric oxide bioavailability as a consequence of oxidative stress.r Mitochondria are critical signalling organelles in the vasculature, which, when dysregulated, become a source of excessive reactive oxygen species; the role of mitochondria-derived oxidative stress in age-related vascular dysfunction is unknown.r We show that a mitochondria-targeted antioxidant, MitoQ, ameliorates vascular endothelial dysfunction in old mice and that these improvements are associated with the normalization of mitochondria-derived oxidative stress and markers of arterial mitochondrial health.r These results indicate that mitochondria-derived oxidative stress is an important mechanism underlying the development of age-related vascular endothelial dysfunction and therefore may be a promising therapeutic target.r Mitochondria-targeted antioxidants represent a novel strategy for preserving healthy vascular endothelial function in primary ageing and preventing age-related CVD in humans.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 ß30% in old (ß27 months) compared with young (ß8 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-rela...

Molecular Strategies for Targeting Antioxidants to Mitochondria: Therapeutic Implications

“…Its acute (ex vivo) administration or chronic supplementation through the animals' drinking water completely restored carotid artery endothelium-dependent dilation in older mice by improving NO bioavailability. The improvements in endothelial function were associated with the normalization of age-related increases in total and mitochondria-derived arterial O 2 -production and oxidative stress (99). MitoQ has also been reported to prevent endotoxin-induced reductions in cardiac mitochondrial and contractile function in rodents (313).…”

“…Having confirmed the viability of the long-term exposure to mitochondria-targeted antioxidants, the following step is to assess whether the amount of accumulated compound is sufficient to act as an antioxidant in vivo. MitoQ has proved effective in several animal models of oxidative stress, such as various CVD settings, including endotoxin-induced cardiac dysfunction (313), age-related arterial endothelial dysfunction (99), cardiac ischemia/reperfusion (2), and doxorubicin-induced cardiac toxicity (40) and was shown to confer protection against an increase in blood pressure in rats that spontaneously develop hypertension (105). In one study, rats were administered 500 lM MitoQ for 2 weeks via their drinking water, after which their hearts were isolated and exposed to ischemia-reperfusion injury in a Langendorff perfusion system.…”

Mitochondrial Impairment in Cerebrovascular Endothelial Cells is Involved in the Correlation between Body Temperature and Stroke Severity

“…LPS [39,40] and rotenone [41,42] are well-known to induce systemic hemodynamic alterations. LPS may reduce interendothelial coupling and arteriolar conduction and cause hemodynamic effects [43].…”

Mitochondria-targeted agents: Future perspectives of mitochondrial pharmaceutics in cardiovascular diseases

“…Graham et al [56] showed that MitoQ protects the development of hypertension, improves endothelial functions and reduces cardiac hypertrophy in young hypertensive rats. MitoQ is also a promising, novel strategy for preserving vascular endothelial function with advancing age and can prevent age-related CVD in mice [57] . However, MitoQ was not useful in protecting oxidative damage to cardiolipin, accumulation of protein carbonyls, activity of mitochondrial respiratory complexes, mtDNA copy number, or damage to mtDNA [58][59][60] .…”