Renewal: Pannexin-1 signaling in abdominal aortic aneurysms

更新：腹主动脉瘤中的 Pannexin-1 信号传导

• 批准号: 10734519
• 负责人: Ashish Kumar Sharma
• 金额: $ 72.22万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-09 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734519
• 关键词: Abdominal Aortic Aneurysm; Aging; Aneurysm; Animals; Aorta; Aortic Aneurysm; Aortic Rupture; Aortitis; Apoptosis; Apoptotic; Binding; Blood Circulation; Cell Death; Cell surface; Cells; Chronic; Chronic Disease; Clinical; Coagulation Process; Collagen; Communication; Cystine; Data; Disease Progression; Elastases; Elastin; Elderly; Endothelial Cells; Enzymes; Equilibrium; Feedback; Fibrin; Functional disorder; Gelatinase A; Genetic; Glutamate Transporter; Goals; Growth; Human; Immune; Impairment; In Vitro; Inflammaging; Inflammation; Inflammatory; Iron; Knockout Mice; Leucocytic infiltrate; Lipid Peroxidation; Lipid Peroxides; Macrophage; Mediating; Mediator; Medical; Methods; Modeling; Molecular; Mus; Nature; Pathogenesis; Pathway interactions; Patients; Phagocytes; Phenotype; Phosphorylation; Physiological; Play; Population; Prevalence; Prevention; Process; Production; Protein S; Receptor Protein-Tyrosine Kinases; Regulation; Resistance; Resolution; Role; Sampling; Signal Transduction; Small Interfering RNA; Smooth Muscle Myocytes; Spironolactone; Sudden Death; Testing; Thinness; Thrombus; Tissues; Tunica Adventitia; Vascular Endothelial Cell; Vascular remodeling; biobank; clinical translation; cytokine; erastin; experimental study; extracellular; in vivo; inhibitor; innovation; insight; knock-down; mortality; mouse model; neutrophil; novel; prevent; receptor; systemic inflammatory response; transcriptomics

PROJECT SUMMARY Abdominal aortic aneurysms (AAA) formation and subsequent aortic rupture can lead to sudden death and is a significant clinical problem with no currently known medical treatments available. The hallmarks of patient AAA include thrombus formation and cell death mechanisms such as apoptosis and neutrophil extracellular traps (NETs). The clearance of dead cell debris is mediated via the process of efferocytosis, by which apoptotic tissue is recognized for engulfment by professional phagocytes (e.g., macrophages) and non-professional phagocytes (e.g., endothelial cells; ECs), and remains to be elucidated in the pathogenesis of AAA. Thus, our hypothesis focuses on the dysregulation of inflammation-resolution pathways that lead to to defective efferocytosis and promote chronic aortic tissue inflammation and vascular remodeling. Our recent study has demonstrated a critical role orchestrated by EC-dependent pannexin-1 (Panx1) channels in causing aortic inflammation and AAA formation. The scientific premise of this proposal focuses on the dysregulation of EC- mediated efferocytosis causing an imbalance of inflammation-resolution via Panx1 activation in AAA progression. Therefore, the central hypothesis in this proposal is that EC efferocytosis is dysregulated due to cleavage of MerTK, a cell surface tyrosine kinase receptor that recognizes apoptotic cells, leading to accumulation of dead cell debris and thrombus formation. Second, our mechanistic studies will dissect the dynamic communication between ECs and macrophages, involving defective EC-mediated efferocytosis leading to excessive iron-mediated cell death (ferroptosis) in macrophages, that collectively feedbacks to cause Panx1 activation and an chronic inflammatory loop. Our supportive data demonstrates that resolution of aortic inflammation is associated with increased EC-dependent MerTK expression and efferocytosis of neutrophils. Furthermore, defective EC-mediated efferocytosis exacerbates ferroptosis in macrophages (via SLC7A11 and Nrf2-signaling) that feedbacks to cause EC-Panx1 activation and eATP release. Collectively, our results suggest that dysregulation of EC-mediated efferocytosis and macrophage-dependent ferroptosis creates a break in the inflammation-resolution process during AAA formation and aortic rupture. We will delineate the proposed studies using the murine elastase-treatment AAA and our innovative aortic rupture model, as well as by analysis of human AAA tissue from our biorepository. Using novel inducible cell-specific genetic knockout mice such as Cdh5Cre-ERT2/MerTKfl/fl, MerTKCR (cleavage-resistant), and Cx3CR1Cre- ERT2/SLC7A11fl/fl mice, we will delineate the previously unknown mechanisms of dysregulated efferocytosis and ferroptosis in activation of Panx1 channels during AAA formation. Our studies will provide novel insight into mechanisms of molecular signaling interactions between ECs and macrophages to define the inflammatory loop between efferocytosis/ferroptosis/Panx1 for the treatment of AAAs and prevention of aortic rupture.

项目摘要 腹主动脉瘤（AAA）形成和随后的主动脉破裂会导致猝死，是一个 重大的临床问题，目前没有已知的医疗治疗。病人AAA的标志 包括血栓形成和细胞死亡机制，例如凋亡和中性粒细胞外陷阱 （网）。死细胞碎片的清除是通过凋亡的过程介导的，凋亡的过程 组织被专业的吞噬细胞（例如巨噬细胞）和非专业的吞噬者认可 吞噬细胞（例如，内皮细胞； EC），在AAA的发病机理中尚待阐明。因此，我们的 假设着重于炎症 - 解决途径的失调，导致有缺陷 肿瘤病并促进慢性主动脉组织炎症和血管重塑。我们最近的研究有 表现出由EC依赖性Pannexin-1（Panx1）渠道策划的关键作用在引起主动脉 炎症和AAA形成。该提案的科学前提重点是EC-的失调 通过AAA中的PANX1激活导致炎症分辨率失衡的介导的肿瘤病 进展。因此，该提议中的核心假设是，EC的肿瘤病因 MERTK的切割，MERTK是一种识别凋亡细胞的细胞表面酪氨酸激酶受体，导致 死细胞碎屑和血栓形成的积累。其次，我们的机械研究将剖析 EC和巨噬细胞之间的动态通信，涉及EC介导的肿瘤有缺陷 导致巨噬细胞中铁介导的细胞死亡过多（铁凋亡），共同反馈到 引起PANX1激活和慢性炎症环。我们的支持数据表明了解决 主动脉炎症与EC依赖性MERTK表达和肿瘤的增加有关 中性粒细胞。此外，巨噬细胞中的EC介导的衰减有缺陷加剧了铁凋亡（通过 SLC7A11和NRF2信号）反馈会导致EC-PANX1激活和EATP释放。总体而言，我们的 结果表明，EC介导的胞吐作用和巨噬细胞依赖性的铁肿瘤的失调 在AAA形成和主动脉破裂期间，在炎症解决过程中产生了突破。我们将 使用鼠弹性酶处理AAA和我们的创新主动脉破裂来描述拟议的研究 模型，以及通过对我们生物座的人类AAA组织的分析。使用新型诱导细胞特异性 遗传基因敲除小鼠，例如CDH5CRE-ERT2/MERTKFL/FL，MERTKCR（抗裂解）和CX3CR1CRE- ERT2/SLC7A11FL/FL小鼠，我们将描述以前未知的失调肿瘤病和 AAA形成过程中PANX1通道激活中的铁凋亡。我们的研究将为您提供新颖的见解 ECS和巨噬细胞之间分子信号传导相互作用的机制来定义炎症 在治疗AAA和预防主动脉破裂的治疗的肿瘤/铁质细胞增多症/PANX1之间的循环。

项目成果

Pharmacologic inhibition by spironolactone attenuates experimental abdominal aortic aneurysms.

• DOI: 10.3389/fcvm.2023.1101389
• 发表时间: 2023
• 期刊: Frontiers in cardiovascular medicine
• 影响因子: 3.6
• 作者: Ladd Z;Su G;Hartman J;Lu G;Hensley S;Upchurch GR Jr;Sharma AK
• 通讯作者: Sharma AK

Sex differences in specialized pro-resolving lipid mediators and their receptors in abdominal aortic aneurysms.

• DOI: 10.1016/j.jvssci.2023.100107
• 发表时间: 2023
• 期刊: JVS-vascular science
• 作者: Filiberto, Amanda C;Leroy, Victoria;Ladd, Zachary;Su, Gang;Elder, Craig T;Pruitt, Eric Y;Lu, Guanyi;Hartman, Joseph;Zarrinpar, Ali;Garrett, Timothy J;Sharma, Ashish K;Upchurch, Gilbert R Jr
• 通讯作者: Upchurch, Gilbert R Jr