Mitochondria-targeted antioxidant therapy with MitoQ ameliorates aortic stiffening in old mice

Abstract

Aortic stiffening is a major independent risk factor for cardiovascular diseases, cognitive dysfunction, and other chronic disorders of aging. Mitochondria-derived reactive oxygen species are a key source of arterial oxidative stress, which may contribute to arterial stiffening by promoting adverse structural changes—including collagen overabundance and elastin degradation—and enhancing inflammation, but the potential for mitochondria-targeted therapeutic strategies to ameliorate aortic stiffening with primary aging is unknown. We assessed aortic stiffness [pulse-wave velocity (aPWV)], ex vivo aortic intrinsic mechanical properties [elastic modulus (EM) of collagen and elastin regions], and aortic protein expression in young (~6 mo) and old (~27 mo) male C57BL/6 mice consuming normal drinking water (YC and OC) or water containing mitochondria-targeted antioxidant MitoQ (250 µM; YMQ and OMQ) for 4 wk. Both baseline and postintervention aPWV values were higher in OC vs. YC (post: 482 ± 21 vs. 420 ± 5 cm/s, P < 0.05). MitoQ had no effect in young mice but decreased aPWV in old mice (OMQ, 426 ± 20, P < 0.05 vs. OC). MitoQ did not affect age-associated increases in aortic collagen-region EM, collagen expression, or proinflammatory cytokine expression, but partially attenuated age-associated decreases in elastin region EM and elastin expression. Our results demonstrate that MitoQ reverses in vivo aortic stiffness in old mice and suggest that mitochondria-targeted antioxidants may represent a novel, promising therapeutic strategy for decreasing aortic stiffness with primary aging and, possibly, age-related clinical disorders in humans. The destiffening effects of MitoQ treatment may be at least partially mediated by attenuation/reversal of age-related aortic elastin degradation.NEW & NOTEWORTHY We show that 4 wk of treatment with the mitochondria-specific antioxidant MitoQ in mice completely reverses the age-associated elevation in aortic stiffness, assessed as aortic pulse-wave velocity. The destiffening effects of MitoQ treatment may be at least partially mediated by attenuation of age-related aortic elastin degradation. Our results suggest that mitochondria-targeted therapeutic strategies may hold promise for decreasing arterial stiffening with aging in humans, possibly decreasing the risk of many chronic age-related clinical disorders.

Suppression of the gut microbiome ameliorates age‐related arterial dysfunction and oxidative stress in mice

“…; Gioscia‐Ryan et al . ). The thoracic aorta was dissected free of surrounding tissue and sectioned into rings 1 mm in length.…”

“…; Gioscia‐Ryan et al . ). The boundaries of the elastin‐dominant region (low force region where curvature is ∼0) of the stress–strain curve were determined by fitting a seventh‐order polynomial equation to the data ( r 2 > 0.99; RStudio, Boston, MA, USA) and then calculating the roots of the equation; the first root was considered the boundary between the very low‐force region and the elastin region, and the second root was considered the boundary between the elastin region and the onset of collagen fibre engagement (Lammers et al .…”

“…; Gioscia‐Ryan et al . ). The elastic modulus of the elastin region was then determined as the slope of a linear equation fit to the stress‐strain data between the two roots.…”

Sex differences in mechanisms of arterial stiffness

“…Preclinical studies have also identified various therapies that have reversed the aging‐associated arterial stiffening in males, such as curcumin (Fleenor et al, ), sodium nitrites (Sindler et al, ), mitochondrial antioxidants (Gioscia‐Ryan et al, ), nicotinamide mononucleotide (de Picciotto et al, ), MR blockade (Kim et al, ), and caloric restriction (Donato et al, ). Several of these therapies—mitochondrial antioxidants (Rossman et al, ), nicotinamide riboside (Martens et al, ), and sodium nitrite (DeVan et al, )—have begun to be translated into studies in healthy older human males and females.…”

Inflammation as a mediator of arterial ageing

“…Mitochondrial targeted antioxidants have been shown to improve both large artery stiffness and EDD in old mice and older adults: however, in contrast to the results with TEMPOL described above, these improvements are largely independent of alterations in circulating and aortic cytokine production (Gioscia‐Ryan et al., , ; Rossman et al., ; Zinovkin et al., ). Mitochondrial targeted antioxidants decrease aortic ICAM in old mice (Zinovkin et al., ), and in rat endothelial cells scavenging of mitochondrial ROS attenuates NFκB activity and inflammatory cytokine production (Ungvari et al., ).…”