Mechanisms linking obesity and abdominal aortic aneurysm

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Obesity has emerged as a risk factor for human and angiotensin II (AngII)-induced abdominal aortic aneurysms (AAA). Obesity is highly prevalent in Veterans; the Veteran population also has high prevalence of other risk factors for AAAs (male sex, smoking, hypertension). To date, no single therapy has proven effective to blunt progressive growth of AAAs, likely due to diverse etiologies underlying AAAs in the human population. Thus, therapies must be individualized to target the relevant risk factor(s), such as obesity and its mechanisms, to effectively ameliorate AAA initiation and progression. We previously reported that obesity promotes AngII-induced AAAs in mice through inflammation in the perivascular adipose tissue. We now have preliminary data demonstrating that whole body deficiency of serum amyloid A (SAA) profoundly reduces AngII-induced AAAs in the setting of obesity. Moreover, our recently published data demonstrate that SAA stimulates macrophage secretion of IL-1β, an inflammatory cytokine implicated in both human and AngII- induced AAAs. In obese subjects, adipocytes become a predominate source of local and systemic SAA. We propose that AngII, periaortic fat and SAA come together in the setting of obesity to create a pro-inflammatory environment immediately adjacent to the abdominal aorta which leads to AAA initiation and expansion. The central hypothesis of this proposal is in the setting of obesity, adipocyte-derived SAA activates the NLRP3 inflammasome in macrophages to promote AAA development in obesity. Aim 1 will test the hypothesis that adipocyte-derived SAA is central in creating the pro-inflammatory environment that promotes AngII-induced AAA formation in obesity. In Aim 2, we will test the hypothesis that adipocyte-derived SAA promotes obesity- induced AAA by activating the NLRP3 inflammasome in macrophages. We have unique mouse models of SAA deficiency as well as transgenic mice with tissue-specific SAA-overexpression in which we can overexpress SAA only in liver or only in fat. We will employ translational therapeutic approaches to prevent the formation and progression of AngII-induced AAAs in obesity. The impact of these studies is that we will identify SAA and periaortic fat burden as biomarkers and risk factors for AAA development and progression in the obese population which may identify precision-targeted AAA therapeutics.