Reactive oxygen species (ROS) have been implicated in the pathogenesis of a number of cardiovascular diseases. Furthermore, recent data from in vitro model systems suggests that mitochondrial ROS production may initiate a vicious cycle termed ROS-induced ROS-release (RI-RR). Whether this phenomenon occurs in vivo or is amplified by aging is not known. We hypothesized that induction of RI-RR by experimentally reducing manganese superoxide dismutase (a mitochondrial antioxidant enzyme) impairs aortic endothelial function and aortic valve function with aging, and that these functional changes would be associated with transcriptional repression of sirtuin family genes, which are known to be associated with aging and age-related diseases. For our studies, we used young (2 mo) and old (>18 mo) MnSOD wild-type (WT) and MnSOD-deficient (HET) mice. In aorta, increasing age significantly impaired vasomotor function (isolated organ chamber baths) in WT mice, but endothelial function was not further impaired in HET mice. Inhibition of NAD(P)H oxidase significantly improved endothelial function in aged WT mice. NAD(P)H oxidase inhibition in HET mice, however, paradoxically worsened endothelial function in young and old animals. Aortic valve function (echocardiography) was unaffected by aging in both WT and HET mice. Interestingly, expression of antioxidant enzymes and multiple sirtuin isoforms (quantitative real-time RT-PCR) were slightly reduced by aging in aorta, but were dramatically reduced in aortic valve. These transcriptional changes were not amplified in either aorta or aortic valve from HET mice. Collectively, our data demonstrate that the transcriptional responses and phenotypes elicited by aging and alterations in mitochondrial antioxidant capacity differ dramatically between aorta and aortic valve. We conclude that reductions in mitochondrial antioxidant capacity do not independently contribute to development of overt cardiovascular disease, and instead suggest that oxidative stress may play a modulatory role in cellular and organismal responses to pathophysiological stimuli that drive age-related cardiovascular disease.
University of Minnesota Master of Science thesis. September 2012. Major: Kinesiology. Advisor: Arthur S. Leon. 1 computer file (PDF); xiii, 116 pages, appendix p. 111-116.
Ross, Carolyn Marie.
Manganese superoxide dismutase and cardiovascular aging phenotypes in mice.
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