All ETDs from UAB

Advisory Committee Chair

Scott W Ballinger

Advisory Committee Members

Shannon Bailey

David Calhoun

Theodore Schurr

Danny R Welch

C Roger White

Document Type

Dissertation

Date of Award

2011

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

While progress has been made in understanding the development and progression of cardiovascular disease (CVD), the mechanisms of CVD risk and initiation are not completely understood. It is widely accepted that CVD is the result of a combination of genetic and environmental factors but it is not known why some populations with otherwise similar risk factors appear more susceptible to CVD than others. It is also known that different strains of laboratory mice have distinct susceptibilities to CVD development. For example, C3H mice are resistant to diet induced atherogenesis whereas C57 animals are susceptible. We have also found that the C3H and C57 mice have genetically distinct mitochondrial DNA (mtDNA) haplotypes and therefore, hypothesize that mitochondrial genetics and function are important factors influencing individual atherogenic susceptibility. We show that C3H and C57 mice not only have different mtDNAs, but also different mitochondrial functions and resistance to mtDNA damage. We have generated a novel mouse model called the Mitochondrial-Nuclear eXchange (MNX) mouse in which a C57 nucleus is switched with a C3H nucleus resulting in mice with the nuclear genome of the C3H and the mtDNA of the C57, or the reciprocal. These MNX mice show differences in mitochondrial function with those animals having C57 mtDNA being more economical (consuming less oxygen to generate ATP) than those mice with the C3H mtDNA. These differences in mitochondrial bioenergetics were found to follow the mtDNA as did differences in cytochrome c oxidase activity. C3H females were bred with apoE-/- males on a C57 background to generate mice with the apoE-/- C57 nuclear genome and C3H mtDNA. Despite higher total cholesterol, these mice displayed lower atherosclerosis compared to apoE-/- mice with C57 mtDNA suggesting that mtDNA significantly impacts atherosclerosis development. Furthermore, developmental exposure to environmental tobacco smoke was shown to increase atherosclerosis which was associated with increased oxidative stress and changes to the mitochondrial proteome that may play a role in atherogenesis. These data suggest that mitochondrial genetics and function play a crucial role in determining individual susceptibility to atherosclerosis potentially by serving as environmental sensors that relay messages to the nucleus.

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