Mechanisms linking obesity and abdominal aortic aneurysm

肥胖已成为人类和血管紧张素II（AngII）诱导的腹主动脉瘤的危险因素 动脉瘤（AAA）。肥胖在退伍军人中非常普遍;退伍军人人群也有很高的患病率， AAA的其他风险因素（男性、吸烟、高血压）。迄今为止，没有单一疗法被证明有效 抑制AAA的进行性生长，可能是由于人群中AAA的病因不同。 因此，治疗必须个体化，以针对相关的风险因素，如肥胖及其 机制，以有效改善AAA的发生和进展。我们之前报道过肥胖 通过血管周围脂肪组织的炎症促进小鼠中AngII诱导的AAA。我们现在有 初步数据表明，全身缺乏血清淀粉样蛋白A（SAA）， AngII诱导的AAAs在肥胖症中的作用此外，我们最近公布的数据表明，SAA 刺激巨噬细胞分泌IL-1β，IL-1 β是一种与人和AngII-2相关的炎性细胞因子， 诱导AAAs。在肥胖受试者中，脂肪细胞成为局部和全身SAA的主要来源。我们 我认为血管紧张素II，主动脉周围脂肪和SAA在肥胖的情况下一起产生促炎性反应， 腹主动脉周围的环境，导致AAA开始和扩张。的 该建议的中心假设是在肥胖的情况下，脂肪细胞衍生的SAA激活NLRP 3 巨噬细胞中的炎性小体促进肥胖症中AAA的发展。目标1将检验以下假设： 脂肪细胞来源的SAA是创造促炎环境的核心，促炎环境促进AngII诱导的 肥胖症中AAA的形成。在目标2中，我们将检验脂肪细胞衍生的SAA促进肥胖的假设- 通过激活巨噬细胞中的NLRP 3炎性体诱导AAA。我们有独特的SAA小鼠模型 缺陷以及具有组织特异性SAA过表达的转基因小鼠， SAA仅存在于肝脏或脂肪中。我们将采用转化治疗方法来防止 和肥胖症中血管紧张素II诱导的AAAs的进展。这些研究的影响是，我们将确定SAA和 主动脉周围脂肪负荷作为肥胖患者AAA发生和进展的生物标志物和风险因素 可以识别精确靶向AAA治疗的人群。

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.