Mechanisms linking obesity and abdominal aortic aneurysm

肥胖已成为人类和血管紧张素II(AngII)诱导的腹主动脉的危险因素 动脉瘤(AAA)。肥胖症在退伍军人中非常普遍；退伍军人人群中也有很高的 AAA的其他危险因素(男性、吸烟、高血压)。到目前为止，还没有一种疗法被证明有效。 抑制AAA的渐进性增长，可能是由于AAA在人类人群中的不同病因所致。 因此，治疗必须个体化，以针对相关的危险因素(S)，如肥胖及其 机制，以有效改善AAA的启动和进展。我们之前曾报道过肥胖 通过血管周围脂肪组织的炎症促进血管紧张素Ⅱ诱导的小鼠AAAs。我们现在有 初步数据显示，全身血清淀粉样蛋白A(SAA)缺乏症显著减少 血管紧张素转换酶诱导肥胖环境中的AAA。此外，我们最近公布的数据表明，SAA 刺激巨噬细胞分泌IL-1β，这是一种与人和血管生成有关的炎性细胞因子 诱导AAA。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 建议在肥胖的背景下，血管紧张素转换酶、腹主动脉周围脂肪和SAA一起产生促炎作用 紧邻腹主动脉的环境，导致腹主动脉的启动和扩张。这个 这一建议的中心假设是在肥胖的背景下，脂肪细胞来源的SAA激活NLRP3 巨噬细胞中的炎性小体促进肥胖AAA的发展。目标1将检验假设 脂肪细胞来源的SAA在创造促进血管紧张素转换酶诱导的促炎环境中起核心作用 AAA在肥胖中的形成。在目标2中，我们将测试脂肪细胞来源的SAA促进肥胖的假设- 通过激活巨噬细胞中的NLRP3炎症体诱导AAA。我们有独特的SAA小鼠模型 我们可以在组织特异性SAA过表达的缺陷小鼠和转基因小鼠 SAA仅见于肝脏或仅见于脂肪。我们将采用转化性治疗方法来防止形成 血管紧张素转换酶诱导的AAA在肥胖中的进展。这些研究的影响是，我们将确定SAA和 腹主动脉周围脂肪负荷是肥胖者腹主动脉硬化发生发展的生物标志物和危险因素 可以识别精确靶向AAA疗法的人群。

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.