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

Gioscia‐Ryan, Rachel A.; Battson, Micah L.; Cuevas, Lauren M.; Eng, Jason; Murphy, Michael P.; Seals, Douglas R.

doi:10.1152/japplphysiol.00670.2017

Cited by 96 publications

(86 citation statements)

References 60 publications

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

Section: Methodsmentioning

confidence: 97%

“…; 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 .…”

Section: Methodsmentioning

confidence: 97%

“…; 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.…”

Section: Methodsmentioning

confidence: 97%

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

Brunt

Gioscia‐Ryan

Richey

et al. 2019

The Journal of Physiology

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140

118

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Key pointsr Age-related arterial dysfunction, characterized by oxidative stress-and inflammation-mediated endothelial dysfunction and arterial stiffening, is the primary risk factor for cardiovascular diseases.Vienna E. Brunt received her PhD in Human Physiology from the University of Oregon in 2016. She is currently a postdoctoral fellow in Dr D. R. Seals' Integrative Physiology of Aging Laboratory at the University of Colorado Boulder. The studies described in the present study represent work carried out as part of an NIH T32 fellowship through the Division of Cardiology at the University of Colorado Denver. Her long-term research goals are to investigate the efficacy of novel interventions for preserving vascular function with ageing, thereby preventing and/or delaying the progression of cardiovascular diseases. Rachel A. Gioscia-Ryan completed her PhD in the Integrative Physiology of Aging Laboratory at the University of Colorado Boulder in 2016 and is currently in medical school at the University of Michigan. She is pursuing a career as a clinician-scientist conducting integrative physiological studies with the aim of improving human health and patient care. * These authors contributed equally to this work.Abstract Oxidative stress-mediated arterial dysfunction (e.g. endothelial dysfunction and large elastic artery stiffening) is the primary mechanism driving age-related cardiovascular diseases. Accumulating evidence suggests the gut microbiome modulates host physiology because dysregulation ('gut dysbiosis') has systemic consequences, including promotion of oxidative stress. The present study aimed to determine whether the gut microbiome modulates arterial function with ageing. We measured arterial function in young and older mice after 3-4 weeks of treatment with broad-spectrum, poorly-absorbed antibiotics to suppress the gut microbiome. To identify potential mechanistic links between the gut microbiome and age-related arterial dysfunction, we sequenced microbiota from young and older mice and measured plasma levels of the adverse gut-derived metabolite trimethylamine N-oxide (TMAO). In old mice, antibiotics reversed endothelial dysfunction [area-under-the-curve carotid artery dilatation to acetylcholine in young: 345 ± 16 AU vs. old control (OC): 220 ± 34 AU, P < 0.01; vs. old antibiotic-treated (OA): 334 ± 15 AU; P < 0.01 vs. OC] and arterial stiffening (aortic pulse wave velocity in young: 3.62 ± 0.15 m s −1 vs. OC: 4.43 ± 0.38 m s −1 ; vs. OA: 3.52 ± 0.35 m s −1 ; P = 0.03). These improvements were accompanied by lower oxidative stress and greater antioxidant enzyme expression. Ageing altered the abundance of gut microbial taxa associated with gut dysbiosis. Lastly, plasma TMAO was higher with ageing (young: 2.6 ± 0.4 μmol L −1 vs. OC: 7.2 ± 2.0 μmol L −1 ; P < 0.0001) and suppressed by antibiotic treatment (OA: 1.2 ± 0.2 μmol L −1 ; P < 0.0001 vs. OC). The results of the present study provide the first evidence for the gut microbiome being an important mediator of age-related arterial dysfunction and ...

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

Section: Methodsmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 97%

See 1 more Smart Citation

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

Brunt

Gioscia‐Ryan

Richey

et al. 2019

The Journal of Physiology

Self Cite

140

118

View full text Add to dashboard Cite

show abstract

“…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.…”

Section: Sex Differences In the Impact Of Cvd Risk Factors On Arteriamentioning

confidence: 99%

Sex differences in mechanisms of arterial stiffness

DuPont

Kenney

Patel

et al. 2019

British J Pharmacology

197

150

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Arterial stiffness progressively increases with aging and is an independent predictor of cardiovascular disease (CVD) risk. Evidence supports that there are sex differences in the time course of aging-related arterial stiffness and the associated CVD risk, which increases disproportionately in postmenopausal women. The association between arterial stiffness and mortality is almost twofold higher in women versus men. The differential clinical characteristics of the development of arterial stiffness between men and women indicate the involvement of sex-specific mechanisms. This review summarizes the current literature on sex differences in vascular stiffness induced by aging, obesity, hypertension, and sex-specific risk factors as well as the impact of hormonal status, diet, and exercise on vascular stiffness in males andfemales. An understanding of the mechanisms driving sex differences in vascular stiffness has the potential to identify novel sex-specific therapies to lessen CVD risk, the leading cause of death in males and females.Large conduit arteries are composed of three layers: (a) the outer tunica adventitia, (b) the middle tunica media, and (c) the inner tunica intima, each of which contributes to the overall stiffness of the vessel wall (Figure 1). The tunica adventitia consists primarily of fibroblasts,

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“…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., ).…”

Section: Interventions To Ameliorate Age‐related Inflammation and Artmentioning

confidence: 97%

Inflammation as a mediator of arterial ageing

Trott

Fadel

2019

Experimental Physiology

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New Findings What is the topic of this review?This review summarizes and synthesizes what is known about the contribution of inflammation to age‐related arterial dysfunction. What advances does it highlight?This review details observational evidence for the relationship of age‐related inflammation and arterial dysfunction, insight from autoimmune inflammatory diseases and their effects on arterial function, interventional evidence linking inflammation and age‐related arterial dysfunction, insight into age‐related arterial inflammation from preclinical models and interventions to ameliorate age‐related inflammation and arterial dysfunction. Abstract Advanced age is a primary risk factor for cardiovascular disease, the leading cause of death in the industrialized world. Two major components of arterial ageing are stiffening of the large arteries and impaired endothelium‐dependent dilatation in multiple vascular beds. These two alterations are major contributors to the development of overt cardiovascular disease. Increasing inflammation with advanced age is likely to play a role in this arterial dysfunction. The purpose of this review is to synthesize what is known about inflammation and its relationship to age‐related arterial dysfunction. This review discusses both the initial observational evidence for the relationship of age‐related inflammation and arterial dysfunction and the evidence that inflammatory autoimmune diseases are associated with a premature arterial ageing phenotype. We next discuss interventional and mechanistic evidence linking inflammation and age‐related arterial dysfunction in older adults. We also attempt to summarize the relevant evidence from preclinical models. Lastly, we discuss interventions in both humans and animals that have been shown to ameliorate age‐related arterial inflammation and dysfunction. The available evidence provides a strong basis for the role of inflammation in both large artery stiffening and impairment of endothelium‐dependent dilatation; however, the specific inflammatory mediators, the initiating factors and the relative importance of the endothelium, smooth muscle cells, perivascular adipose tissue and immune cells in arterial inflammation are not well understood. With the expansion of the ageing population, ameliorating age‐related arterial inflammation represents an important potential strategy for preserving vascular health in the elderly.

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

Cited by 96 publications

References 60 publications

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

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

Sex differences in mechanisms of arterial stiffness

Inflammation as a mediator of arterial ageing

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