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）诱导的腹主动脉的危险因素 动脉瘤（AAA）。肥胖在退伍军人中非常普遍。退伍军人人口也很高 AAAS（男性，吸烟，高血压）的其他危险因素。迄今为止，尚无单一疗法证明有效 AAAS的渐进式增长可能是由于人口中AAA的潜在病因引起的。 这是针对相关危险因素的疗法，例如肥胖及其 机制，有效地改善了AAA计划和进展。我们以前报道了肥胖症 通过在血管周围脂肪组织中注射来促进小鼠中的Angii诱导的AAA。我们现在有 初步数据表明，血清淀粉样蛋白A（SAA）的全身缺乏症可深刻降低 Angii在肥胖症的环境中引起了AAA。此外，我们最近发布的数据表明SAA 刺激IL-1β的巨噬细胞分泌，这是一种在人和血管中实现的炎性细胞因子 诱导的AAA。在肥胖的受试者中，脂肪细胞成为局部和系统性SAA的主要来源。我们 提议Angii，周围的脂肪和SAA在肥胖症的情况下聚集在一起创造促炎性 紧邻腹主动脉的环境，导致AAA倡议和扩展。这 该提议的中心假设在于肥胖的环境，脂肪细胞衍生的SAA激活NLRP3 巨噬细胞中的炎症体，以促进肥胖症中的AAA发育。 AIM 1将检验以下假设 脂肪细胞衍生的SAA对于创建促进Angii诱导的促炎环境至关重要 肥胖中的AAA形成。在AIM 2中，我们将检验以下假设：脂肪细胞衍生的SAA促进肥胖症 - 通过激活巨噬细胞中的NLRP3炎症体来诱导AAA。我们有独特的SAA鼠标模型 缺乏症以及具有组织特异性SAA超过表达的转基因小鼠，我们可以过表达 SAA仅在肝脏或仅在脂肪中。我们将采用翻译的治疗方法来防止形成 Angii引起的肥胖症的AAA的进展。这些研究的影响是，我们将确定SAA和 肥胖的生物标志物和危险因素，肥胖的脂肪伯恩作为生物标志物和风险因素 可以确定靶向精确的AAA疗法的人群。