Browning of perivascular adipose tissue protects against thoracic aortic aneurysm

血管周围脂肪组织褐变可预防胸主动脉瘤

• 批准号: 10580855
• 负责人: YUQING Eugene CHEN
• 金额: $ 58.62万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580855
• 关键词: Acceleration; Address; Adipocytes; Adipose tissue; Affect; Aneurysm; Aorta; Aortic Aneurysm; Apoptosis; Atherosclerosis; Blood Vessels; Brown Fat; Cardiac; Cardiovascular Diseases; Characteristics; Chest; Clinical; Clinical Treatment; Clinical Trials; Coculture Techniques; Conditioned Culture Media; Data; Development; Disease; Dissection; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Generations; Genes; Genetic Predisposition to Disease; Health; Heritability; Homeostasis; Human; Hypertension; In Vitro; Induction of Apoptosis; Inflammation; Inflammatory; Infusion procedures; Knockout Mice; Knowledge; Lesion; Life; Mediating; Metabolic Diseases; Modeling; Morbidity - disease rate; Mus; Nitrogen Dioxide; Operative Surgical Procedures; Other Genetics; Outcome; Oxidative Stress; Pathology; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase II Clinical Trials; Process; Property; Proteins; Repression; Research; Risk Adjustment; Role; Rupture; Signal Transduction; Smooth Muscle Myocytes; Testing; Thoracic Aortic Aneurysm; Transgenic Mice; Vascular Diseases; Vascular Smooth Muscle; Work; adipokines; clinical translation; epidemiology study; gain of function; genetic approach; in vivo; inflammatory marker; knock-down; loss of function; mortality; nitrated conjugated linoleic acid; novel; novel drug class; novel therapeutic intervention; overexpression; paracrine; perioperative mortality; pharmacologic; prevent; programs; repaired; resistin

PROJECT SUMMARY/ABSTRACT Thoracic aortic aneurysm (TAA) is a life-threatening disease and has a high mortality rate if rupture occurs. Currently, apart from endovascular or open surgery repair, no drug has been demonstrated to be effective for TAA treatment. Even though some patients with TAA have evidence of a heritable aortopathy, about 75% of TAA patients have severe aortic damage without a clear genetic etiology. The scant mechanistic knowledge is limiting the development of medications for the treatment of TAA, thus highlighting a pressing need for better understanding TAA formation and progression. Aorta is naturally surrounded by perivascular adipose tissue (PVAT). Recent large-scale epidemiological studies demonstrated that PVAT was highly associated with a significantly higher adjusted risk of all-cause cardiac mortality. We and others documented that brown-like PVAT contributes to vascular homeostasis in health, while whitening of PVAT is dysfunctional and contributes to development of the vascular diseases. A causal relationship between PVAT and TAA and the underlying mechanisms remain unknown. Our preliminary studies indicate that the PVAT near the TAA lesion in patients lost brown characteristics, and that TAA formation was dramatically increased in mice that lack normal PVAT, suggesting that dysfunctional PVAT is associated with TAA. The conditioned medium from PVAT of TAA patients induced apoptosis and inflammation in human aortic smooth muscle cells, suggesting that signaling from PVAT can cause loss of vascular smooth muscle cells (VSMC) in the aorta, which may promote TAA lesion. It is unknown whether browning of PVAT could protect against TAA. PR-domain containing 16 (PRDM16) is a determinant of browning gene programs. We show that PRDM16 expression in PVAT of TAA patients is significantly reduced when compared to that in normal PVAT. PRDM16 inhibited resistin expression in PVAT. We found that nitrated conjugated linoleic acid (NO2-CLA) induced the browning of human PVAT adipocytes by mediating PRDM16 signaling. Based on these data, we hypothesize that PRDM16-mediated PVAT browning prevents TAA formation. We will determine that 1) PRDM16 in PVAT prevents and reverses TAA in mice; 2) PRDM16 inhibits TAA by regulating PVAT crosstalk with VSMC; 3) NO2-CLA prevents TAA by targeting PRDM16. Outcomes will demonstrate that a previously unrecognized process involving loss of browning features in PVAT promotes TAA formation through crosstalk to VSMC. This work will accelerate clinical translation of a nitro-fatty acid-based treatment for TAA targeting PVAT homeostasis with this new class of drugs, currently on clinical trials for other diseases.

项目摘要/摘要 胸动脉瘤（TAA）是一种威胁生命的疾病，如果发生破裂，死亡率很高。 目前，除了血管内或开放手术维修外，尚未证明没有药物有效 TAA治疗。即使某些TAA患者有可遗传性主动脉疾病的证据，但约有75％ TAA患者的主动脉损伤严重，没有明显的遗传病因。机械知识很少 限制用于治疗TAA的药物的开发，从而突出了迫切的需求 了解TAA的形成和进展。主动脉自然被血管周围脂肪组织包围 （PVAT）。最近的大规模流行病学研究表明，PVAT与A高度相关 全因心脏死亡率的调整风险明显更高。我们和其他人记录了类似棕色的 PVAT在健康方面有助于血管稳态，而PVAT的美白功能失调，并且有贡献 发育血管疾病。 PVAT和TAA与基础之间的因果关系 机制仍然未知。我们的初步研究表明，患者的TAA病变附近的PVAT 失去棕色特征，而缺乏正常PVAT的小鼠，TAA的形成大大增加了， 表明功能失调的PVAT与TAA有关。来自TAA的PVAT的条件培养基 患者诱导人主动脉平滑肌细胞的凋亡和炎症，表明信号传导 来自PVAT可能会导致主动脉中血管平滑肌细胞（VSMC）的丧失，这可能会促进TAA 病变。未知PVAT的褐变是否可以防止TAA。含有16的PR域 （PRDM16）是褐变基因程序的决定因素。我们表明pRDM16在TAA的PVAT中的表达 与正常PVAT相比，患者显着降低。 PRDM16抑制了抵抗素的表达 在PVAT。我们发现硝化的共轭亚油酸（NO2-CLA）诱导了人类PVAT的褐变 通过介导PRDM16信号传导的脂肪细胞。基于这些数据，我们假设PRDM16介导 PVAT褐变可防止TAA形成。我们将确定1）PVAT中的PRDM16可防止和逆转 在小鼠中taa; 2）PRDM16通过与VSMC调节PVAT串扰来抑制TAA； 3）NO2-CLA可防止TAA 针对PRDM16。结果将表明，涉及丢失的先前未认识的过程 PVAT中的褐变特征通过串扰到VSMC促进TAA组。这项工作将加速 使用这种新的新靶向PVAT稳态的基于硝基脂肪酸的临床翻译 药物类别，目前正在针对其他疾病进行临床试验。