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.

项目概要 腹主动脉瘤 (AAA) 形成和随后的主动脉破裂可导致猝死，是一种 目前尚无可用的已知医学治疗方法的重大临床问题。 AAA患者的特征 包括血栓形成和细胞死亡机制，例如细胞凋亡和中性粒细胞胞外陷阱 （网络）。死细胞碎片的清除是通过胞吞作用过程介导的，通过该过程，细胞凋亡 组织被专业吞噬细胞（例如巨噬细胞）和非专业吞噬细胞吞噬 吞噬细胞（例如内皮细胞；EC），并且 AAA 的发病机制仍有待阐明。因此，我们的 假说侧重于炎症消解途径的失调，从而导致缺陷 胞吞作用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 证明了 EC 依赖性 pannexin-1 (Panx1) 通道在引起主动脉粥样硬化中发挥着关键作用 炎症和 AAA 形成。该提案的科学前提集中于 EC-的失调 AAA 中介导的胞吞作用通过 Panx1 激活导致炎症消退失衡 进展。因此，该提案的中心假设是 EC 胞吞作用因以下因素而失调： MerTK（一种识别凋亡细胞的细胞表面酪氨酸激酶受体）的裂解，导致 死细胞碎片的积累和血栓的形成。其次，我们的机制研究将剖析 EC 和巨噬细胞之间的动态通讯，涉及有缺陷的 EC 介导的胞吞作用 导致巨噬细胞中铁介导的细胞死亡（铁死亡）过多，从而集体反馈到 导致 Panx1 激活和慢性炎症循环。我们的支持性数据表明，解决方案 主动脉炎症与 EC 依赖性 MerTK 表达增加和胞吞作用相关 中性粒细胞。此外，有缺陷的 EC 介导的胞吞作用会加剧巨噬细胞中的铁死亡（通过 SLC7A11 和 Nrf2 信号传导）反馈导致 EC-Panx1 激活和 eATP 释放。总的来说，我们的 结果表明 EC 介导的胞吞作用和巨噬细胞依赖性铁死亡的失调 在 AAA 形成和主动脉破裂期间，炎症消退过程会中断。我们将 描述使用小鼠弹性蛋白酶治疗 AAA 和我们创新的主动脉破裂的拟议研究 模型，以及对我们生物样本库中的人体 AAA 组织进行分析。使用新型诱导细胞特异性 基因敲除小鼠，例如 Cdh5Cre-ERT2/MerTKfl/fl、MerTKCR（抗切割）和 Cx3CR1Cre- ERT2/SLC7A11fl/fl 小鼠，我们将描述以前未知的胞吞作用失调机制和 AAA 形成过程中 Panx1 通道激活中的铁死亡。我们的研究将提供新的见解 EC 和巨噬细胞之间的分子信号相互作用机制来定义炎症 胞吞作用/铁死亡/Panx1 之间的循环，用于治疗 AAA 和预防主动脉破裂。

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