Mechanisms of renin angiotensin modulation in thoracic aortic aneurysms

摘要 胸主动脉瘤(TAA)是一种常见的、临床上无症状的主动脉扩张症。然而， 这种疾病的并发症--如主动脉夹层和破裂--是突然和致命的。因为有 目前尚无有效的药物治疗来预防或逆转主动脉扩张，所有胸主动脉患者 动脉瘤最终将需要手术修复。 马凡综合征是由纤维蛋白-1突变引起的，纤维蛋白-1是一种大的细胞外基质蛋白，与 弹性蛋白结构和主动脉完整性。我们的项目建议使用马凡综合征模型小鼠来 探讨TAAS的发病机制。我们已经证明，TAA存在于血管紧张素受体(AT1a)中 受体)依赖的方式。马凡综合征AT1a受体是如何被激活的 知识。 AT1a受体被其主要效应肽血管紧张素II典型地激活。它也可以 以不依赖配体的方式被激活。我们假设马凡综合征的AT1a受体是 以依赖血管紧张素Ⅱ的方式激活。此外，我们假设内源性血管紧张素转换酶的耗竭 通过抑制AT1a受体活性，充分抑制马凡综合征患者TAA的发展。 为了验证这一假设，我们将确定血管紧张素原反义是否导致血管紧张素转换酶耗竭。 寡核苷酸治疗可减轻主动脉扩张、主动脉中层重构和主动脉AT1a受体 活动。我们还将使用大型电子健康记录数据集进行回溯性临床研究，以 确定血管形成抑制、血管紧张素受体阻断或β-受体阻断是否与 马凡综合征患者对TAA的防护。 总之，这个项目的完成将提供对分子机制的更好的理解。 马凡综合征相关胸主动脉瘤发病机制的研究。

ABSTRACT Thoracic aortic aneurysms (TAAs) are a common, clinically-silent dilatation of the aorta. However, complications of this disease - such as aortic dissection and rupture - are sudden and deadly. Because there is currently no validated medical therapy to prevent or reverse aortic dilation, all patients with thoracic aortic aneurysms will eventually need surgical repair. Marfan syndrome is caused by mutations in fibrillin-1, a large extracellular matrix protein responsible for elastin structure and aortic integrity. Our project proposes the use of Marfan syndrome model mice to investigate the pathogenesis of TAAs. We have shown that TAAs occur in an angiotensin receptor (AT1a receptor) dependent manner. How AT1a receptors are activated in Marfan syndrome is a gap in current knowledge. AT1a receptors are canonically activated by its main effector peptide, angiotensin II. It can also be activated in a ligand independent manner. We hypothesize that AT1a receptors in Marfan syndrome are activated in an AngII dependent manner. Furthermore, we hypothesize that depletion of endogenous AngII sufficiently attenuates TAA development in Marfan syndrome through inhibition of AT1a receptor activity. To test this hypothesis, we will determine if AngII depletion by angiotensinogen antisense oligonucleotide administration attenuates aortic dilation, aortic medial remodeling, and aortic AT1a receptor activity. We will also perform a retrospective clinical study using a large electronic health record dataset to determine if inhibition of AngII formation, angiotensin receptor blockade, or beta-blockade are associated with protection against TAA in Marfan syndrome patients. Altogether, completion of this project will provide a better understanding of the molecular mechanism behind Marfan syndrome associated thoracic aortic aneurysm pathogenesis.