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 胸主动脉瘤(TAA)是一种危及生命的疾病，如果发生破裂，死亡率很高。 目前，除了血管内或开放手术修复外，还没有任何药物被证明对 TAA治疗。尽管一些患有TAA的患者有证据表明存在遗传性动脉病变，但约75%的 TAA患者有严重的主动脉损伤，没有明确的遗传病因。所缺乏的机械知识是 限制治疗TAA的药物的开发，从而突出了迫切需要更好地 了解TAA的形成和发展。主动脉自然被血管周围的脂肪组织包围。 (PVAT)。最近的大规模流行病学研究表明，PVAT与一种 调整后的全原因心脏死亡风险显著增加。我们和其他人记录了像棕色一样的 PVAT有助于健康中的血管动态平衡，而PVAT的美白功能失调，并有助于 与血管疾病的发展密切相关。PVAT和TAA之间的因果关系及其潜在的 机制仍不清楚。我们的初步研究表明，患者TAA病变附近的PVAT 失去棕色特征，在缺乏正常PVAT的小鼠中TAA的形成显著增加， 提示PVAT功能障碍与TAA有关。TAA的PVAT条件培养液 患者诱导了人主动脉平滑肌细胞的凋亡和炎症，提示信号转导 PVAT可导致主动脉内血管平滑肌细胞(VSMC)的丢失，从而促进TAA 损伤。目前尚不清楚PVAT的褐变是否能保护其免受TAA侵染。PR域，包含16个 (PRDM16)是褐变基因程序的决定因素。我们发现PRDM16在TAA的PVAT中的表达 与正常PVAT相比，患者显著减少。PRDM16抑制抵抗素表达 在PVAT中。我们发现，硝化共轭亚油酸(NO2-CLA)可引起人PVAT的褐变 脂肪细胞通过介导PRDM16信号。根据这些数据，我们假设PRDM16介导的 PVAT褐变可防止TAA的形成。我们将确定1)PVAT中的PRDM16预防和逆转 2)PRDM16通过调节PVAT与VSMC的串扰来抑制TAA；3)NO2-CLA通过以下途径抑制TAA 目标是PRDM16。结果将证明，以前未被认识到的过程涉及损失 PVAT中的褐变特征通过与VSMC的串扰促进TAA的形成。这项工作将加快 以硝基脂肪酸为基础的靶向PVAT动态平衡的TAA的临床翻译 一类药物，目前正在进行其他疾病的临床试验。