Reactive oxygen species and telomere dysfunction: Investigating the underlying mechanisms of aging and related diseases

Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality in western countries. The underlying mechanism of the disorder remains unknown, but ROS and telomere dysfunction have been independently implicated in atherogenesis, and are common elements among the major risks factors. However, the relationship between ROS, telomere biology and atherosclerosis has not been adequately examined. Nor is it clear whether the relationship between ROS and telomere dysfunction play a causative or correlative role in atherosclerosis. Based on scientific evidence that ROS modulate telomeres, we hypothesized that telomere dysfunction is a crucial downstream target of oxidative stress in the development of atherosclerosis.;In Chapter I, we characterized the telomere biology of aortic smooth muscle cells (ASMC) from mouse models haploid deficient in mitochondrial (SOD2+/-) and cytoplasmic (SOD1+/-) superoxide dismutase. The SOD2+/- model exhibits properties associated with atherosclerosis. We found rapid telomere erosion in SOD2+/- ASMC despite elevated telomerase activity. Furthermore, we observed increased oxidative DNA damage and dysfunctional telomeres in SOD2+/- ASMC compared to wildtype (WT). Our results suggest telomere erosion was not a consequence of nuclear export of telomerase protein subunit but most likely the result of increased oxidative damage at the telomeres.;Additionally, we studied the effects of anti-atherosclerotic compounds on telomerase. In chapter III, we treated SOD2+/- and WT ASMC with NADPH oxidase inhibitors and estrogen. We found NADPH oxidase inhibitors modulate telomerase activity as well as confirmed the ability of estrogen to up regulate telomerase. Lastly, in chapter IV, we examined the effects of oxidatively modified deoxyguanosine triphosphate on telomerase activity in vitro and observed a modest effect suggesting telomerase is not remarkably sensitive to this nucleotide.;These findings demonstrate that chronic oxidative stress can cause telomere dysfunction in the vasculature system, particularly ASMC. Our studies provide a basis to better understand the relationship between oxidative stress and telomere dysfunction, and the roles they might play in atherogenesis. Moreover, our observation of elevated telomerase in SOD2+/- ASMC is quite promising, as it provides an opportunity to further study if telomerase promotes proliferation in SOD2+/- ASMC in a telomere independent manner.