Mechanisms linking obesity and abdominal aortic aneurysm

肥胖与腹主动脉瘤的联系机制

• 批准号: 10266037
• 负责人: LISA R TANNOCK
• 金额: --
• 依托单位: VA MEDICAL CENTER - LEXINGTON, KY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266037
• 关键词: Abdominal Aortic Aneurysm; Acute; Adipocytes; Adipose tissue; Age; Angiotensin II; Angiotensins; Biological Markers; C57BL/6 Mouse; Cause of Death; Consumption; Data; Development; Etiology; Fatty acid glycerol esters; Gender; Goals; Growth; Health; High Fat Diet; High Prevalence; Human; Hyperlipidemia; Hypertension; Inflammasome; Inflammation; Inflammatory; Interleukin-1 beta; Link; Liver; Mediator of activation protein; Modeling; Mus; Obese Mice; Obesity; Overweight; Phase; Population; Production; Protein Isoforms; Proteins; Publishing; Reporting; Resistance; Risk Factors; Role; Ruptured Abdominal Aortic Aneurysm; Serum amyloid A protein; Signal Transduction; Smoking; Source; Stimulus; Testing; Therapeutic; Tissues; Transgenic Mice; United States; United States Department of Veterans Affairs; Veterans; abdominal aorta; age group; cytokine; high risk; human very old age (85+); hypercholesterolemia; inflammatory milieu; macrophage; male; military veteran; mouse model; novel; novel therapeutic intervention; obese person; overexpression; prevent; sex; tool; vascular inflammation

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.

肥胖已成为人类和血管紧张素 II (AngII) 诱发的腹主动脉瘤的危险因素 动脉瘤（AAA）在退伍军人中非常普遍；退伍军人人群中肥胖症的患病率也很高。 AAA 的其他危险因素（男性、吸烟、高血压）迄今为止，尚无单一疗法被证明有效。 抑制 AAA 的逐渐增长，这可能是由于人类 AAA 的病因多种多样。 因此，治疗必须个体化，以针对相关的危险因素，例如肥胖及其相关因素。 机制，以有效改善 AAA 的发生和进展，我们之前报道过肥胖。 我们现在发现，AngII 通过血管周围脂肪组织的炎症促进小鼠体内 AngII 诱导的 AAA。 初步数据表明，全身缺乏血清淀粉样蛋白 A (SAA) 会显着降低 此外，我们最近发表的数据表明，SAA 会导致肥胖。 刺激巨噬细胞分泌 IL-1β，这是一种与人类和 AngII-相关的炎症细胞因子 在肥胖受试者中，脂肪细胞成为局部和全身 SAA 的主要来源。 提出 AngII、主动脉周围脂肪和 SAA 在肥胖的情况下共同产生促炎性 紧邻腹主动脉的环境导致 AAA 起始和扩张。 该提案的中心假设是在肥胖的情况下，脂肪细胞衍生的 SAA 激活 NLRP3 巨噬细胞中的炎性体促进肥胖中 AAA 的发展。目标 1 将检验以下假设： 脂肪细胞衍生的 SAA 在创造促进 AngII 诱导的促炎环境中发挥着核心作用 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 NLRP3 炎性体诱导 AAA 我们拥有独特的 SAA 小鼠模型。 缺陷以及具有组织特异性 SAA 过度表达的转基因小鼠，我们可以在其中过度表达 SAA 仅在肝脏或仅在脂肪中，我们将采用转化治疗方法来防止形成。 AngII 诱导的 AAA 在肥胖中的作用和进展 这些研究的影响是我们将识别 SAA 和 AAA。 主动脉周围脂肪负荷作为肥胖者 AAA 发生和进展的生物标志物和危险因素 可以识别精准靶向 AAA 疗法的人群。