Vascular smooth muscle cell ferroptosis and abdominal aortic aneurysm

血管平滑肌细胞铁死亡与腹主动脉瘤

基本信息

批准号：
10733477
负责人：
Yanhong Guo
金额：
$ 68.91万
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：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10733477
关键词：
Abdominal Aortic Aneurysm Address Adult Alleles Aneurysm Angiotensin II Animal Model Aorta Aortic Aneurysm Apoptosis Arteries Attenuated Blood Vessels Cell Death Cell Death Induction Characteristics Clinical Medicine Contractile Proteins Coupled Cytoprotection Data Data Set Databases Death Rate Development Diameter Disease Dissection Elastases Embryo Enzymes Extracellular Matrix Degradation Gene Delivery Gene Expression Genes Genetic Growth Human Human Genetics Hyperlipidemia In Vitro Incidence Inflammatory Response Inhibition of Apoptosis Iron Ischemia Knock-in Mouse Knock-out Knockout Mice Lesion Life Lipid Peroxidation Lipid Peroxides LoxP-flanked allele Malignant Neoplasms Membrane Lipids Modeling Molecular Mus Neurodegenerative Disorders Nicotine Nicotinic Acids Operative Surgical Procedures Oxidative Stress Palmitic Acids Pathogenesis Pathologic Pathway interactions Patients Pentoxifylline Pharmaceutical Preparations Pharmacological Treatment Phenotype Play Reduced Glutathione Regulation Reperfusion Therapy Research Resistance Risk Risk Factors Role Rupture Ruptured Abdominal Aortic Aneurysm Ruptured Aneurysm Smoking Smooth Muscle Myocytes Solid Stimulus Structure Testing Thoracic aorta Transgenic Mice Vascular Smooth Muscle abdominal aorta adenoviral mediated cigarette smoke epidemiology study gain of function gender difference glutathione peroxidase high risk hypercholesterolemia in vivo inhibitor knock-down long chain fatty acid loss of function mortality mouse model new therapeutic target novel novel strategies novel therapeutic intervention overexpression prevent protective effect protein expression repaired response single-cell RNA sequencing tissue injury vascular inflammation

项目摘要

PROJECT SUMMARY/ABSTRACT Abdominal aortic aneurysm (AAA) is a permanent abdominal aorta expansion with high mortality but limited treatment options. Currently, there are no effective clinical medicines to prevent, delay, or reverse the growth or rupture of AAA, except an open or endovascular surgical repair for symptomatic aneurysms or aneurysms at high risk for rupture. Vascular smooth muscle cells (VSMC) are crucial in maintaining vascular wall integrity and function, while VSMC depletion is a characteristic feature of AAA. Ferroptosis is a type of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides. Smoking is a well- established AAA risk factor, and cigarette smoke extract induces VSMC ferroptosis. Glutathione peroxidase 4 (GPX4) has been identified as a critical inhibitor of ferroptosis and apoptosis. Human genetics and Gene Expression Omnibus database have demonstrated that decreased GPX4 expression is associated with an increased risk of AAA. Our preliminary studies demonstrate that GPX4 is significantly reduced in the aorta of AAA patients and animal models. Nicotine, a well-established AAA risk factor, reduced GPX4 and SMC contractile protein expression. We posit that AAA risk factors can result in VSMC death via an underappreciated pathway, i.e., ferroptosis in the artery resulting in AAA formation and rupture. We generated VSMC-specific Gpx4 knockout mice (Gpx4SMKO) by crossing Myh11-Cre with Gpx4flox/flox mice. When subjected to aneurysm induction by angiotensin II (Ang II) coupled with hypercholesterolemia, about 50% of Gpx4SMKO mice died due to AAA rupture. The incidence rate and maximal diameters in Gpx4SMKO mice were larger than in Gpx4flox/flox control mice. Specific Aim 1 will define the protective effects of VSMC-specific GPX4 in AAA using our novel VSMC-selective GPX4 transgenic mice. We will also examine the effects of VSMC-specific Gpx4 knockout using a different murine model with perivascular application of elastase, an AAA model that does not produce rupture. Aim 2 will determine the GPX4-dependent protective mechanisms in VSMC using gain- and loss-of-function strategies. We will examine the effects of GPX4 on AAA-relevant stimuli-induced cell death, VSMC phenotypic switch, and inflammatory responses in primary human and mouse abdominal aortic smooth muscle cells. Aim 3 will define that local activation of GPX4 attenuates AAA pathogenesis by enhancing VSMC capacity of resistance to pathologic factors. Further, we will examine whether the GPX4 activator protects against aneurysm development and rupture. Successful completion of the proposed studies will establish novel mechanisms regulating VSMC loss and vascular inflammation in AAA, which are likely to advance our understanding of the AAA formation and ultimately lead to novel strategies for treating AAA.

项目概要/摘要腹主动脉瘤（AAA）是一种永久性腹主动脉扩张，死亡率高但有限治疗方案。目前，临床上尚无有效的药物可以预防、延缓或逆转该病的生长。或 AAA 破裂，但针对有症状的动脉瘤或动脉瘤进行的开放式或血管内手术修复除外破裂的风险很高。血管平滑肌细胞 (VSMC) 对于维持血管壁完整性至关重要和功能，而 VSMC 耗竭是 AAA 的一个特征。铁死亡是一种程序化细胞死亡依赖于铁，其特征是脂质过氧化物的积累。吸烟是一种很好的确定了 AAA 危险因素，香烟烟雾提取物可诱导 VSMC 铁死亡。谷胱甘肽过氧化物酶4 (GPX4) 已被确定为铁死亡和细胞凋亡的关键抑制剂。人类遗传学和基因 Expression Omnibus 数据库证明 GPX4 表达减少与 AAA 风险增加。我们的初步研究表明，GPX4 在主动脉中显着减少。 AAA 患者和动物模型。尼古丁是一种公认的 AAA 风险因素，可减少 GPX4 和 SMC 收缩蛋白表达。我们认为 AAA 风险因素可通过以下途径导致 VSMC 死亡：未被充分认识的途径，即动脉铁死亡导致 AAA 形成和破裂。我们生成了通过 Myh11-Cre 与 Gpx4flox/flox 小鼠杂交获得 VSMC 特异性 Gpx4 敲除小鼠 (Gpx4SMKO)。什么时候血管紧张素 II (Ang II) 诱发动脉瘤并伴有高胆固醇血症，约 50% Gpx4SMKO 小鼠因 AAA 破裂而死亡。 Gpx4SMKO小鼠的发病率和最大直径比 Gpx4flox/flox 对照小鼠大。具体目标 1 将定义 VSMC 特定的保护作用使用我们新型 VSMC 选择性 GPX4 转基因小鼠在 AAA 中使用 GPX4。我们还将研究以下影响使用不同的小鼠模型进行 VSMC 特异性 Gpx4 敲除，并在血管周围应用弹性蛋白酶（一种 AAA）不产生破裂的模型。目标 2 将确定 GPX4 依赖性保护机制 VSMC 使用功能获得和丧失策略。我们将研究 GPX4 对 AAA 相关的影响刺激诱导的细胞死亡、VSMC 表型转换以及原代人类和小鼠的炎症反应小鼠腹主动脉平滑肌细胞。目标 3 将定义 GPX4 的本地激活会减弱 AAA 通过增强VSMC抵抗病理因素的能力来发病。进一步，我们将检查 GPX4 激活剂是否可以防止动脉瘤发展和破裂。圆满完成了拟议的研究将建立调节 AAA 中 VSMC 损失和血管炎症的新机制，这可能会增进我们对 AAA 形成的理解，并最终带来新的策略治疗AAA。