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.

项目总结

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