Role of Rage in Bicuspid Aortic Valve Symdrome

愤怒在二叶式主动脉瓣综合征中的作用

• 批准号: 9762185
• 负责人: Giovanni Ferrari
• 金额: $ 40.2万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-08 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762185
• 关键词: Address; Affect; Algorithms; Anatomy; Aneurysm; Angiotensin II; Aorta; Aortic Aneurysm; Aortic Valve Stenosis; Apoptosis; Architecture; Area; Assimilations; Basic Science; Biomechanics; Blood Vessels; Body Weight; Caliber; Cardiac; Caring; Cells; Chronic; Clinical; Clinical Management; Congenital Heart Defects; Coupled; Cytoskeleton; Data; Diagnostic; Dilatation - action; Dissection; Down-Regulation; Enrollment; Event; Excision; Fibronectins; Functional disorder; Genes; Genetic; Goals; Guidelines; HMGB1 gene; Heart Diseases; Histologic; Homeostasis; Human; Image Analysis; Imaging Techniques; In Vitro; Individual; Infusion procedures; Injections; Letters; Life; Literature; Manuscripts; Measurement; Medial; Mediating; Mediator of activation protein; Methodology; Modeling; Molecular; Mus; Operative Surgical Procedures; Outcome; Oxidative Stress; Pathology; Patient risk; Patients; Pharmacology; Phenotype; Physicians; Population; Porphyrins; Predisposition; Preventive treatment; Process; Production; Public Health; Rage; Reactive Oxygen Species; Regulation; Regulatory Pathway; Reporting; Resected; Risk; Risk stratification; Role; Rupture; Scientist; Signal Transduction; Small Interfering RNA; Smooth Muscle Myocytes; Specimen; Structure; Support Groups; Surface; Surgeon; Syndrome; Testing; Therapeutic; Thoracic Aortic Aneurysm; Tissues; United States National Institutes of Health; Vascular Diseases; Vascular Smooth Muscle; ascending aorta; base; bicuspid aortic valve; circulating biomarkers; connective tissue growth factor; high risk; human tissue; in vivo; mimetics; model design; mouse model; myocardin; novel; novel strategies; patient population; personalized medicine; premature; receptor for advanced glycation endproducts; reconstruction; tool; transcriptome sequencing

SUMMARY. Bicuspid Aortic Valve (BAV) is the most common congenital heart defect in the US and is associated with frequent and premature occurrence of aortic stenosis (AS) and ascending thoracic aortic aneurysm (TAA). It has been estimated that 30-50% of BAV patients will require surgical intervention in their life for valvulopathy, aortopathy or both. While AS is a degenerative process that span over a decade, a dissection or rupture of the aorta has devastating consequences. One of today’s major clinical controversies among cardiologists and cardiac surgeons is the management of BAV patients for the risk of adverse aortic events. According to the the current guidelines, BAV patients are risk-stratified using metric measurements obtained by imaging techniques. Although aortic diameter, expansion rate, and ratio of aortic area/diameter to body weight/surface are the current indications for elective surgical intervention, they are imperfect predictors of aortic dissection and rupture. The lack of correlation between diameter and histologic abnormality in the setting of BAV highlights the inadequacy of diameter alone as a reason for aortic resection. New approaches to study aortic wall homeostasis are clearly needed, and new methodologies to implement imaging techniques based on aortic wall microstructure should be prioritized. In doing so, this application addresses areas that the NIH has identified as important, understudied topics, including the characterization of pre-onset identification and preventive treatment of vascular diseases. Failing to do so, will lead to the continued use of inadequate clinical managements of BAV patients with suboptimal care. This application fills this gap. Our goal is to investigate BAV predisposition to adverse aortic events and to unveil the diagnostic and therapeutic potentials of the AGE/ROS/myocardin axis. Aim 1 will determine BAV predisposition to proximal aortopathies and is association to altered AGE/ROS/myocardin signaling in human VSMCs and aortic wall tissues. BAV patients will be enrolled and risk-stratified according to sRAGE level and analyzed ex vivo for dysfunction of the aortic wall by biomechanical testing. BAV-derived VSMC plasticity will be determined in vitro by dissecting RAGE/ROS/myocardin signaling using novel SOD mimetics (MnTE-2-PyP5+ and MnTnBuOE-2-PyP5+), anti- and pre-miR143, and myocardin siRNA. Endpoints and readouts will include ECM remodeling, VSMC phenotype, proliferation, and apoptosis. Cell- and tissue-derived data will be coupled with circulating markers and imaging analysis for the risk stratification of BAV patients including different BAV anatomical configuration. Notably, we have the ability to test over a thousand non surgical patients. Thus, our data move beyond purely basic science questions and begin to address questions about clinical management based on new risk- stratification tools. Aim 2 will modulate AGE/ROS/myocardin signaling in vivo and determine its impact on aortic wall remodeling in BAV and TAV murine models. AGE/ROS/myocardin axis will be dissected at multiple level in vivo by implementing pharmacological approaches and selected genetic backgrounds. Capitalizing on Myocd conditional (SM-MyHC-CreERT/MyocdF/F), RAGE-/-, and eNOS-/- (selected for BAV presence by echo), we will test the role of Ang II chronic infusion on AV and ascending aortic remodeling modulating miR143 (Pre-miR143 and LNAmiR143) or oxidative stress (Mn-porphyrins). AV function and aortic dilation will be tested echocardiographically; aortic remodeling will be determined by VSMC phenotype and ECM remodeling. Thus, this application has two important outcomes for public health: in the short term, it will provide physicians and scientists a tool (in addition to the current imaging techniques), to identify a patient population at high risk of valve and vascular pathologies. In the long term, it will provide mechanistic information on the cellular and molecular events leading to ascending aortopathies, which will be integral to personalized therapies for high-risk individuals.

摘要 二叶式主动脉瓣（BAV）是美国最常见的先天性心脏病， 主动脉瓣狭窄（AS）和升胸主动脉瘤（TAA）的频繁和过早发生。它有 据估计，30-50%的BAV患者在其生命中需要手术干预瓣膜病， 或两者皆有。虽然AS是一个跨越十多年的退行性过程，但动脉瘤的解剖或破裂是一个非常重要的因素。 大动脉会带来毁灭性的后果当今心脏病专家和 心脏外科医生是BAV患者的主动脉不良事件风险管理。根据该 在目前的指南中，使用通过成像技术获得的度量测量值对BAV患者进行风险分层。 尽管主动脉直径、扩张率和主动脉面积/直径与体重/表面积的比值是目前的 对于选择性外科干预的适应症，它们是主动脉夹层和破裂的不完全预测因子。 在BAV背景下，直径和组织学异常之间缺乏相关性，这突出了 直径不足单独作为主动脉切除术的原因。研究主动脉壁稳态的新方法 和新的方法来实现基于主动脉壁微结构的成像技术 应该优先考虑。在这样做的过程中，该应用程序解决了NIH确定为重要的领域， 未充分研究的主题，包括发病前识别和预防性治疗的特点， 血管疾病如果不这样做，将导致继续使用不适当的BAV临床管理 护理欠佳的患者。该应用程序填补了这一空白。 我们的目标是调查BAV易患不良主动脉事件，并揭示诊断和治疗方法。 AGE/ROS/myocardin轴。目标1将确定BAV近端病变的易感性 并且与人VSMC和主动脉壁组织中改变的AGE/ROS/心肌蛋白信号传导相关。BAV 患者将被招募并根据血清学水平进行风险分层，并离体分析其功能障碍。 主动脉壁生物力学测试。BAV衍生的VSMC可塑性将在体外通过解剖 使用新的SOD模拟物（MnTE-2-PyP 5+和MnTnBuOE-2-PyP 5+）、抗-NH3/ROS/心肌素信号传导， 和前-miR 143，和心肌蛋白siRNA。终点和读数将包括ECM重塑、VSMC 表型、增殖和凋亡。细胞和组织来源的数据将与循环标志物相结合 和影像学分析，用于BAV患者的风险分层，包括不同的BAV解剖结构。 值得注意的是，我们有能力测试超过1000名非手术患者。因此，我们的数据不仅仅是 基础科学问题，并开始解决基于新风险的临床管理问题- 分层工具。目的2将在体内调节AGE/ROS/myocardin信号通路，并确定其对主动脉粥样硬化的影响。 BAV和TAV鼠模型中的壁重塑。AGE/ROS/myocardin轴将在多个水平解剖， 通过实施药理学方法和选定的遗传背景在体内进行。利用Myocd 条件性（SM-MyHC-CreERT/MyocdF/F）、NOS-/-和eNOS-/-（通过超声选择BAV存在），我们将 测试Ang II慢性输注对AV和升主动脉重构调节miR 143（Pre-miR 143）的作用 和LNAmiR 143）或氧化应激（Mn-卟啉）。将测试AV功能和主动脉扩张 超声心动图;主动脉重塑将通过VSMC表型和ECM重塑来确定。 因此，这项应用对公共卫生有两个重要的结果：在短期内，它将为医生提供 和科学家的工具（除了目前的成像技术），以确定患者人群的高风险， 瓣膜和血管病变。从长远来看，它将提供有关细胞和 分子事件导致上升性脊椎病，这将是高风险患者个性化治疗的组成部分。 个体

项目成果

Biomarkers of Calcific Aortic Valve Disease.

• DOI: 10.1161/atvbaha.116.308615
• 发表时间: 2017-04
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Small A;Kiss D;Giri J;Anwaruddin S;Siddiqi H;Guerraty M;Chirinos JA;Ferrari G;Rader DJ
• 通讯作者: Rader DJ