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

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

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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.

项目摘要/摘要腹主动脉瘤（AAA）是一种永久性腹主动脉膨胀，死亡率高但有限治疗选择。目前，没有有效的临床药物可以预防，延迟或扭转增长或AAA破裂，除了有症状性动脉瘤或动脉瘤的开放或血管内手术修复外破裂的高风险。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的特征。铁凋亡是一种编程细胞死亡取决于铁，其特征是脂质过氧化物的积累。吸烟是一个很好的建立的AAA危险因素，香烟烟雾提取物诱导VSMC铁肉芽作用。谷胱甘肽过氧化物酶4 （GPX4）已被确定为脂肪吞噬和凋亡的关键抑制剂。人遗传学和基因表达综合数据库已证明降低的GPX4表达与增加了AAA的风险。我们的初步研究表明，GPX4在主动脉的主动脉中显着降低 AAA患者和动物模型。尼古丁是一个良好的AAA风险因素，降低了GPX4和SMC 收缩蛋白表达。我们认为AAA风险因素可能会导致VSMC死亡被低估的途径，即动脉的铁凋亡，导致AAA形成和破裂。我们生成了 VSMC特异性GPX4敲除小鼠（GPX4SMKO）通过将MYH11-CR与GPX4Flox/Flox小鼠跨越。什么时候血管紧张素II（ANG II）与高胆固醇血症结合，约50％ GPX4SMKO小鼠由于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。特定目标1将定义VSMC特异性的保护作用 AAA中的GPX4使用我们的新型VSMC选择性GPX4转基因小鼠。我们还将研究使用不同的鼠模型，使用不同的鼠模型弹性酶，AAA的VSMC特异性GPX4敲除不会产生破裂的模型。 AIM 2将确定与GPX4相关的保护机制 VSMC使用获得和功能丧失策略。我们将研究GPX4对AAA相关的影响刺激引起的细胞死亡，VSMC表型转换和原代人的炎症反应小鼠腹主动脉平滑肌细胞。 AIM 3将定义GPX4的局部激活减弱AAA 通过增强对病理因素的抗性能力来提高发病机理。此外，我们将检查 GPX4激活剂是否可以防止动脉瘤的发育和破裂。成功完成拟议的研究将建立调节AAA中VSMC损失和血管炎症的新型机制，这可能会提高我们对AAA组的理解，并最终导致新颖的策略治疗AAA。