Objectives: The goal of this new application is to elucidate novel mechanisms by which leukocytes contribute to vascular disease, particularly in the setting of the low grade inflammation triggered by obesity. Vascular disease in the setting of obesity is extremely common in the US veteran population. Research Plan: To assess the role of neutrophil extracellular traps (NETs) on vascular disease, mouse models of diet-induced obesity and obesity-induced atherosclerosis will be used. In vitro models will address the mechanisms by which NETs are induced. Therapies designed to inhibit NET formation will be tested with multiple relevant vascular endpoints, including endothelial function, thrombosis, and atherosclerosis. Finally, the role of a leukocyte ligand in mediating adhesive interactions resulting in NET formation will be determined as this may serve as an upstream therapeutic target. Methods: The strategy to accomplish the objectives will be to use mouse models and in vitro assays to explore mediators of adipose tissue inflammation and the vascular risk associated with obesity.
Aim 1 will determine the effect of obesity on neutrophil recruitment and NET formation in adipose tissue depots, bone marrow, and circulating neutrophils from obese mice. In vitro experiments will be performed to determine the effect of obese adipose tissue components on NET formation and will consider the systemic effects of obesity on activation of bone marrow-derived neutrophils.
Aim 2 will test the therapeutic effects of NET dissolution or NET prevention on vascular disease endpoints exacerbated by obesity, including endothelial function, atherosclerosis, and thrombosis.
Aim 3 will determine the contribution of P-selectin glycoprotein ligand-1 (Psgl1) towards neutrophil recruitment and NET formation in obese adipose tissue.
Complications of atherosclerosis such as myocardial infarction and stroke remain the leading cause of morbidity and mortality in the veteran population. Recent widespread implementation of prevention programs and pharmacologic treatments appear to be effective in reducing the incidence of cardiovascular morbidity and mortality. However, this progress is now being neutralized as the obesity epidemic begins to impact cardiovascular events. The veteran population is particularly susceptible to the development of obesity with the majority of veterans now overweight or obese. By uncovering the inflammatory pathways by which obese adipose tissue affects vascular disease, new therapies can be developed and applied to the obese veteran population at risk for complications of atherosclerosis. Reducing the morbidities associated with vascular disease, such as myocardial infarction and stroke, will have a major beneficial effect on the health of the veteran population.
