Date of Award

Spring 1-1-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Integrative Physiology

First Advisor

Douglas R. Seals

Second Advisor

Robert S. Mazzeo

Third Advisor

William C. Byrnes

Fourth Advisor

Christopher D. Link

Fifth Advisor

Adam J. Chicco

Abstract

Advancing age is a primary risk factor for cardiovascular diseases (CVD), due primarily to development of age-related arterial dysfunction, including arterial endothelial dysfunction and stiffening of large elastic arteries. A key cellular mechanism underlying age-related arterial dysfunction is oxidative stress, a state in which cellular production of reactive oxygen species (ROS) such as superoxide exceeds endogenous antioxidant defense capabilities.

Vascular mitochondria are emerging as critical regulators of arterial function. Vascular mitochondria produce physiological levels of ROS (mtROS) for signaling, but mitochondrial dysfunction is characterized by excessive mtROS production. Thus, vascular mitochondria represent a key potential source of arterial oxidative stress; however, the role of mtROS in age-related arterial dysfunction has been unknown. Accordingly, the purpose of this dissertation was to determine the role of mitochondria-derived oxidative stress in arterial aging and to investigate the therapeutic potential of a mitochondria-targeted antioxidant, MitoQ, to ameliorate age-related arterial dysfunction.

In arteries of old mice, mitochondrial superoxide production was ~3 times greater than in arteries of young mice, and this was associated with arterial endothelial dysfunction, measured as a reduction in nitric oxide-mediated endothelium-dependent dilation (EDD). Acute, ex-vivo application of MitoQ to reduce mitochondrial oxidative stress abolished the age-associated impairment in EDD. Moreover, chronic, in vivo MitoQ supplementation (4 weeks in drinking water) in old mice completely restored EDD to levels similar to those of young mice, accompanied by normalization of age-related alterations in protein markers of mitochondrial health measured in whole arteries.

Arterial aging in mice was also characterized by elevated large-elastic artery stiffness, assessed in vivo as aortic pulse-wave velocity (aPWV). MitoQ supplementation in old mice reduced aPWV to levels similar to those of young mice and this was at least partially mediated by attenuation of the age-related reduction in arterial elastin content.

Together, these results indicate that mitochondrial oxidative stress is a key mechanism underlying age-related arterial dysfunction. These studies demonstrate that reducing mitochondrial oxidative stress with the targeted antioxidant MitoQ restores EDD and reduces arterial stiffness in old mice, underscoring the therapeutic potential for mitochondria-targeted strategies to reduce mitochondrial oxidative stress, improve arterial function, and reduce CVD risk in humans.

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