title: Mitochondrial quality control and age-associated arterial stiffening.
abstract: Stiffening of large elastic arteries with age increases the risk of cardiovascular diseases (CVD), but the underlying mechanisms are incompletely understood. We investigated the role of mitochondrial quality control (QC, i.e., mitophagy and biogenesis) in arterial stiffening with aging. In C57BL6 mice, aging was associated with impaired aortic expression of mitochondrial QC mediators, greater activation of the mitochondrial redox/stress sensor p66shc, elevated superoxide production and increased arterial stiffness-as indicated by ~25% higher aortic pulse wave velocity (aPWV). In old mice, supplementation with trehalose, a nutraceutical reported to enhance mitophagy, normalized mitochondrial QC markers, p66shc activation and superoxide production, and reduced aPWV and aortic collagen I (a structural protein that confers stiffness). In vitro experiments suggested that mitochondrial QC processes were enhanced in the aortas from old trehalose-treated mice, and in aortic rings studied ex vivo, both aging and treatment with the mitochondrial stressor rotenone were associated with increases in p66shc activation and intrinsic mechanical stiffness, whereas co-incubation with trehalose prevented these effects. Taken together, these findings suggest that mitochondrial stress/dysfunction as a result of impaired mitochondrial QC contributes to large elastic artery stiffening with age. Enhancing mitochondrial QC with agents such as trehalose may be a novel strategy for reducing age-associated arterial stiffness and CVD.
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA. Electronic address: thomas.larocca@colorado.edu.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: LaRocca
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Hearon
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA.
authors.forename: Grant D
authors.initials: GD
authors.lastname: Henson
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA. Electronic address: seals@colorado.edu.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Seals
mesh_terms: D000367:Age Factors; D000375:Aging; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001018:Aortic Diseases / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D024042:Collagen Type I / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D063306:Mitophagy; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D063177:Pulse Wave Analysis; D012402:Rotenone / Q000494:pharmacology; D055765:Shc Signaling Adaptor Proteins / Q000378:metabolism; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013481:Superoxides / Q000378:metabolism; D046509:Tissue Culture Techniques; D014199:Trehalose / Q000494:pharmacology; D059289:Vascular Stiffness / Q000187:drug effects
chemical_list: D024042:Collagen Type I; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D012402:Rotenone; D013481:Superoxides; D014199:Trehalose
keywords: Collagen; Mitochondrial biogenesis; Mitophagy