Metabolic Syndrome & Pathobiology of Aortic Aneurysms

点击翻译按钮获取中文摘要

Since the metabolic syndrome is present in about a quarter of American adults and almost half of those over the age of 60, it is not surprising that nearly 50% of patients with abdominal aortic aneurysms (AAAs) fulfill the criteria for this syndrome. However, it is surprising that essentially nothing is known about how the presence of this syndrome affects the clinical manifestations of AAAs. AAAs are a common form of vascular disease characterized by chronic aortic wall inflammation and connective tissue destruction, depletion of medial smooth muscle cells, and impaired connective tissue repair. Patients with AAAs exhibit aortic tissue production and elevated circulating levels of pro-inflammatory proteins that may serve as biomarkers of disease activity. Reparative biological processes, such as recruitment of bone marrow-derived vascular progenitor cells and neovascularization, might be capable of stabilizing aneurysm tissue. Many of these events are recapitulated in mouse models of AAAs. Many of the same pro-inflammatory proteins that circulate in patients with AAAs are also increased in people with the metabolic syndrome. This project will test the hypothesis that the presence of the metabolic syndrome adversely impacts the clinical course of people with AAAs. Several pro-inflammatory mediators affecting AAA biology may also be affected through signaling pathways triggered by ATM (Ataxia Telangiectasia Mutated) and data from Project 1 show that this protein can be activated by chloroquine. We will also test the hypothesis that the ATM pathway modulates inflammation to affect anuerysm formation. We will address the following aims: 1-Determine if the presence of metabolic syndrome in humans influences inflammatory markers and a clinically relevant outcome (persistent aneurysm expansion following endovascular aneurysm repair). 2-Establish if the presence of metabolic syndrome in humans influences aortic tissue recruitment and circulating levels of vascular progenitor cells capable of connective tissue repair. 3-Evaluate if ATM deficiency in mice affects the development of experimental AAAs and if ATM activation with chloroquine can suppress experimental AAAs. This project has the potential to transform the care of people with the metabolic syndrome by establishing the mechanisms by which this disorder may affect clinical outcomes following surgical repair of aneurysms.