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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/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，尚无药物被证明对治疗有效。 TAA治疗。尽管一些 TAA 患者有遗传性主动脉病的证据，但大约 75% TAA 患者有严重的主动脉损伤，但没有明确的遗传病因。缺乏机械知识限制了治疗 TAA 的药物的开发，从而凸显了迫切需要更好的药物了解 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 与全因心脏死亡的调整后风险显着升高。我们和其他人记录了类似棕色的 PVAT 有助于健康的血管稳态，而 PVAT 的美白功能失调并有助于血管疾病的发展。 PVAT 和 TAA 之间的因果关系及其基础机制仍不清楚。我们的初步研究表明，患者 TAA 病变附近的 PVAT 失去了棕色特征，并且缺乏正常 PVAT 的小鼠中 TAA 的形成显着增加，表明功能失调的 PVAT 与 TAA 相关。 TAA 的 PVAT 条件培养基患者诱导人主动脉平滑肌细胞凋亡和炎症，表明信号传导 PVAT 引起的血管平滑肌细胞 (VSMC) 损失可能会促进 TAA 病变。目前尚不清楚 PVAT 的褐变是否可以防止 TAA。 PR 结构域包含 16 (PRDM16) 是褐变基因程序的决定因素。我们发现 PRDM16 在 TAA 的 PVAT 中表达与正常PVAT相比，患者显着减少。 PRDM16 抑制抵抗素表达在PVAT中。我们发现硝化共轭亚油酸 (NO2-CLA) 会诱导人 PVAT 褐变脂肪细胞通过介导 PRDM16 信号传导。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 可以预防和逆转小鼠TAA； 2) PRDM16通过调节PVAT与VSMC的串扰抑制TAA； 3) NO2-CLA 通过以下方式预防 TAA 针对 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。这项工作将加速基于硝基脂肪酸的 TAA 治疗的临床转化，以 PVAT 稳态为目标类药物，目前正在进行其他疾病的临床试验。