Telomere uncapping and arterial dysfunction: Novel mechanism and implications for aging

点击翻译按钮获取中文摘要

 DESCRIPTION (provided by applicant): Advancing age is the primary risk factor for cardiovascular diseases, and arterial dysfunction is a critical contributor to this increased disease risk. The proposed studies will explore the novel hypothesis that age- associated arterial telomere dysfunction is an underlying mechanism for increased arterial inflammation and dysfunction with aging. We hypothesize that telomere dysfunction, characterized by telomere uncapping, triggers cell senescence via the p53/p21 pathway that results in increased inflammatory signaling and ultimately leading to augmented large artery stiffness and endothelial dysfunction. We will address these hypotheses by utilizing mouse and endothelial cell culture models of aging, as well as inducible systemic and endothelial specific models of telomere uncapping. Additionally, using a transgenic mouse model of greater systolic blood pressure and pulse pressure and in vitro arterial and tissue culture models of circumferential stress, we will determine if increases in circumferential wall stretch is a critical stimulus for te induction of telomere uncapping. These results will reveal a novel mechanism underlying age-associated arterial dysfunction and disease risk, as well as provide critical evidence for future studies to determine therapeutic targets to reduce chronic arterial inflammation. This is a clinically relevant and important goal given the prevalence of cardiovascular disease among older adults, the increasing age of our population and its associated morbidity, mortality, and health care burden.