Date of Award

Spring 1-1-2012

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Integrative Physiology

First Advisor

Douglas R. Seals

Second Advisor

Robert S. Mazzeo

Third Advisor

Anthony J. Donato

Abstract

Aging is the major risk factor for the development of cardiovascular diseases (CVD). Pathological changes to arteries lead to vascular dysfunction and contribute to CVD events. Endothelial dysfunction and large elastic artery stiffness are two major vascular changes that occur with age, and precede the manifestation of overt CVD. SIRT1, a member of the sirtuins, a family of enzymes associated with improved longevity and health span, have reduced activity and/or expression with age, which correlates with vascular dysfunction in humans. This suggests that declines in SIRT1 activity may contribute to age-related vascular dysfunction, and activation of SIRT1 may improve vascular function in older adults. The purpose of this dissertation was to assess the effects of chronic SIRT1 activation with the small molecule activator SRT1720 on vascular function and to determine the mechanisms by which SIRT1 elicits beneficial effects in old and young male mice. Aortic SIRT1 protein expression and activity were reduced with age, and restored with SRT1720 treatment in old mice. Endothelium-dependent dilation (EDD), a measure of vascular endothelial function, was reduced in old vehicle-treated mice compared with young control mice (p < 0.05), but was restored in old mice with SIRT1 activation (p < 0.05). Arterial stiffness, as indicated by pulse wave velocity, was higher in old versus young mice (p < 0.01), and was selectively reduced with SIRT1 activation in old mice. Aortic superoxide production was higher in old mice treated with vehicle compared with young control animals, but was reduced with SIRT1 activation in old mice (both p < 0.05). SRT1720 treatment in old mice also increased arterial antioxidant enzyme expression compared to old vehicle-treated animals. Levels of inflammatory cytokines were increased in old vehicle-treated versus young control mice, whereas SIRT1 activation partially normalized arterial inflammation in old animals. In conclusion, SIRT1 activation ameliorated the age-related decline in vascular endothelial function and reduced large elastic artery stiffness, and this was associated by normalization of arterial oxidative stress and inflammation. These results indicate that SIRT1 activation may represent a novel therapy for reducing age-associated vascular dysfunction, thereby reducing the associated increase in CVD risk and mortality.

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