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

• 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
• 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

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.

项目总结/摘要 腹主动脉瘤（AAA）是一种永久性腹主动脉扩张，死亡率高， 治疗方案。目前，没有有效的临床药物来预防，延迟或逆转生长 或AAA破裂，但对症状性动脉瘤或动脉瘤进行开放或血管内手术修复除外， 破裂风险高。血管平滑肌细胞（VSMC）在维持血管壁完整性方面至关重要 而VSMC耗竭是AAA的特征性特征。铁凋亡是一种程序化细胞 依赖铁的死亡，特征是脂质过氧化物的积累。吸烟是一种很好的- 建立AAA危险因素，香烟烟雾提取物诱导VSMC铁凋亡。谷胱甘肽过氧化物酶4 GPX 4是铁凋亡和细胞凋亡的重要抑制剂。人类遗传学和基因 表达综合数据库已经证明GPX 4表达的降低与 AAA风险增加我们的初步研究表明，GPX 4在主动脉中显著减少， AAA患者和动物模型。尼古丁是一种公认的AAA风险因素，可降低GPX 4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： 被低估的途径，即，动脉中的铁下垂导致AAA形成和破裂。我们产生 通过Myh 11-Cre与Gpx 4flox/flox小鼠杂交获得VSMC特异性Gpx 4敲除小鼠（Gpx 4SMKO）。当 血管紧张素II（Ang II）与高胆固醇血症联合诱导动脉瘤，约50% Gpx 4SMKO小鼠由于AAA破裂而死亡。Gpx 4 SMKO小鼠的发生率和最大直径 比Gpx 4flox/flox对照小鼠大。具体目标1将定义VSMC特异性 使用我们的新型VSMC选择性GPX 4转基因小鼠在AAA中的GPX 4。我们还将研究 使用血管周围应用弹性蛋白酶（AAA）的不同鼠模型进行VSMC特异性Gpx 4敲除 不产生破裂的模型。目的2将确定GPX 4依赖的保护机制， VSMC使用增益和功能丧失策略。我们将研究GPX 4对AAA相关的 刺激诱导的细胞死亡，VSMC表型转换，和炎症反应，在原代人类和 小鼠腹主动脉平滑肌细胞。目的3将定义GPX 4的局部激活减弱AAA 通过增强VSMC对病理因素的抵抗能力而致病。此外，我们将研究 GPX 4激活剂是否能防止动脉瘤的发展和破裂。成功完成 提出的研究将建立调节AAA中VSMC损失和血管炎症的新机制， 这可能会促进我们对AAA形成的理解，并最终导致新的策略， 治疗AAA。