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Background: Dietary high salt (HS) intake has a strong impact on cardiovascular diseases. Here, we investigated the link between HS-aggravated immune responses and the development of hypertensive vascular disease., Methods: ApolipoproteinE-deficient mice were transiently treated with HS (1% NaCl) via drinking water for 2 weeks, followed by a washout period, and subsequent Ang II (angiotensin II) infusion (1000 ng/kg per min for 10 days) to induce abdominal aortic aneurysms/dissections and inflammation., Results: While transient HS intake alone triggered nonpathologic infiltration of activated T cells into the aorta, subsequent Ang II infusion increased mortality and the incidence of abdominal aortic aneurysms/dissections and atherosclerosis compared with hypertensive control mice. There were no differences in blood pressure between both groups. In transient HS-treated hypertensive mice, the aortic injury was associated with increased inflammation, accumulation of neutrophils, monocytes, CD69 + CD4 + T cells, as well as CD4 + and CD8 + memory T cells. Mechanistically, transient HS intake increased expression levels of aortic RORγt as well as splenic CD4 + T H 17 and CD8 + T C 1 T cells in Ang II-treated mice. Isolated aortas of untreated mice were incubated with supernatants of T H 17, T H 1, or T C 1 cells polarized in vitro under HS or normal conditions which revealed that secreted factors of HS-differentiated T H 17 and T C 1 cells, but not T H 1 cells accelerated endothelial dysfunction., Conclusions: Our data suggest that transient HS intake induces a subclinical T-cell-mediated aortic immune response, which is enhanced by Ang II. We propose a 2-hit model, in which HS acts as a predisposing factor to enhance hypertension-induced T H 17 and T C 1 polarization and aortic disease., Competing Interests: None.

Background: Developing a molecular signature associated with CD4 + T cell infiltration is essential for identifying biomarkers in abdominal aortic aneurysms (AAA). Establishing such a signature is vital for improving diagnostic accuracy and therapeutic strategies for AAA. This study focuses on CD4 + T cells, which are pivotal in the immune microenvironment of AAA, to pinpoint key targets., Methods and Results: We identified CD4 + T cell-related biomarkers in AAA using bulk and single-cell RNA sequencing data from the GEO database. We employed CIBERSORT to assess immune cell infiltration and applied weighted gene co-expression network analysis and differential expression analyses to pinpoint key genes. A nomogram and related score were developed based on these genes. Single-cell RNA sequencing further analyzed their expression across cell types, and KEGG/GO analyses were conducted for candidate genes. Four genes (NUPR1, CCL4L2, CCL3L3, MMP9) were identified finally. Validation via qPCR and immunohistochemistry showed NUPR1 downregulation in aneurysms and an inverse relationship with CD4 + T cells infiltration. Immunofluorescence results indicated NUPR1 was mainly expressed in the cytoplasm of vascular smooth muscle cells (VSMCs). After VSMCs-specific overexpression of NUPR1 via adeno-associated virus, the AAA diameter decreased, while treatment with the NUPR1 nuclear translocation inhibitor ZZW-115 hydrochloride had no effect on AAA size. Overexpression of NUPR1 in VSMCs suppresses the migration of CD4 + T cells., Conclusion: The four-gene signature accurately predicts CD4 + T cell infiltration in AAA patients and may serve as a clinical index. NUPR1 could be a therapeutic target for the interaction between CD4 + T cells and AAA., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Abdominal aortic aneurysm (AAA) is a macrovascular disease with high morbidity and mortality in the elderly. The limitation of the current management is that most patients can only be followed up until the AAA diameter increases to a threshold, and surgical intervention is recommended. The development of preventive and curative drugs for AAA is urgently needed. Macrophage-mediated immune inflammation is one of the key pathological links in the occurrence and development of AAA., Aims: This review article aims to evaluate the impact of immunometabolism on macrophage biology and its role in AAA., Methods: We analyze publications focusing on the polarization and metabolic reprogramming in macrophages as well as their potential impact on AAA, and summarize the potential interventions that are currently available to regulate these processes., Results: The phenotypic and functional changes in macrophages are accompanied by significant alterations in metabolic pathways. The interaction between macrophage polarization and metabolic pathways significantly influences the progression of AAA., Conclusion: Macrophage polarization is a manifestation of the gross dichotomy of macrophage function into pro-inflammatory killing and tissue repair, that is, classically activated M1 macrophages and alternatively activated M2 macrophages. Macrophage functions are closely linked to metabolic changes, and the emerging field of immunometabolism is providing unique insights into the role of macrophages in AAA. It is essential to further investigate the precise metabolic changes and their functional consequences in AAA-associated macrophages., (© 2024 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Background: Macrophages are key regulators of the inflammatory and innate immune responses. Researchers have shown that aberrant expression of macrophages contributes to the development of abdominal aortic aneurysms (AAA). However, a comprehensive bibliometric analysis exploring the research status and knowledge mapping of this area is lacking. This study aimed to explore the research status, knowledge mapping and hotspots of macrophages in AAA research from a bibliometric perspective., Methods: In this study, we retrieved articles published between 2000 and 2022 on macrophages associated with AAA research from the Web of Science Core Collection (WoSCC) database. The retrieved literature data were further analyzed using Citespace and VOSviewer software., Results: A total of 918 qualified publications related to AAA-associated macrophages were retrieved. The number of publications in this field has been increasing annually. China and the United States were the 2 main drivers in this field, contributing to more than 64% of the publications. In addition, the US had the most publications, top institutions, and expert researchers, dominating in research on macrophages in AAA. The Harvard University was the most productive institution, with 60 publications. The journal with the most publications was Arteriosclerosis, Thrombosis, and Vascular Biology (86). Daugherty Alan was the most prolific author (28 publications) and he was also the most cited co- author. Furthermore, the exploration of established animal models, macrophage-related inflammatory-microenvironment, macrophage-related immune mechanism, clinical translation and molecular imaging research remained future research directions in this field., Conclusions: Our findings offered new insights for scholars in this field. They will help researchers explore new directions for their work., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Abdominal aortic aneurysm (AAA) poses a significant health risk and is influenced by various compositional features. This study aimed to develop an artificial intelligence-driven multiomics predictive model for AAA subtypes to identify heterogeneous immune cell infiltration and predict disease progression. Additionally, we investigated neutrophil heterogeneity in patients with different AAA subtypes to elucidate the relationship between the immune microenvironment and AAA pathogenesis., Methods: This study enrolled 517 patients with AAA, who were clustered using k-means algorithm to identify AAA subtypes and stratify the risk. We utilized residual convolutional neural network 200 to annotate and extract contrast-enhanced computed tomography angiography images of AAA. A precise predictive model for AAA subtypes was established using clinical, imaging, and immunological data. We performed a comparative analysis of neutrophil levels in the different subgroups and immune cell infiltration analysis to explore the associations between neutrophil levels and AAA. Quantitative polymerase chain reaction, Western blotting, and enzyme-linked immunosorbent assay were performed to elucidate the interplay between CXCL1, neutrophil activation, and the nuclear factor (NF)-κB pathway in AAA pathogenesis. Furthermore, the effect of CXCL1 silencing with small interfering RNA was investigated., Results: Two distinct AAA subtypes were identified, one clinically more severe and more likely to require surgical intervention. The CNN effectively detected AAA-associated lesion regions on computed tomography angiography, and the predictive model demonstrated excellent ability to discriminate between patients with the two identified AAA subtypes (area under the curve, 0.927). Neutrophil activation, AAA pathology, CXCL1 expression, and the NF-κB pathway were significantly correlated. CXCL1, NF-κB, IL-1β, and IL-8 were upregulated in AAA. CXCL1 silencing downregulated NF-κB, interleukin-1β, and interleukin-8., Conclusion: The predictive model for AAA subtypes demonstrated accurate and reliable risk stratification and clinical management. CXCL1 overexpression activated neutrophils through the NF-κB pathway, contributing to AAA development. This pathway may, therefore, be a therapeutic target in AAA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Inflammation is a key component in the development of abdominal aortic aneurysm (AAA), yet insights into the roles of immune cells and their interactions in this process are limited., Methods: Using single-cell RNA transcriptomic analysis, we deconstructed the CD45 + cell population in elastase-induced murine AAA at the single-cell level. We isolated each group of immune cells from murine AAA tissue at different time points and divided them into several subtypes, listed the remarkable differentially expressed genes, explored the developmental trajectories of immune cells, and demonstrated the interactions among them., Results: Our findings reveal significant differences in several immune cell subsets, including macrophages, dendritic cells, and T cells, within the AAA microenvironment compared with the normal aorta. Especially, conventional dendritic cell type 1 exclusively existed in the AAA tissue rather than the normal aortas. Via CellChat analysis, we identified several intercellular communication pathways like visfatin, which targets monocyte differentiation and neutrophil extracellular trap-mediated interaction between neutrophils and dendritic cells, which might contribute to AAA development. Some of these pathways were validated in human AAA., Conclusions: Despite the absence of external pathogenic stimuli, AAA tissues develop a complex inflammatory microenvironment involving numerous immune cells. In-depth studies of the inflammatory network shall provide new strategies for patients with AAA., Competing Interests: None.

Background: The purpose of this study is to investigate the causal effect and potential mechanisms between telomere length and abdominal aortic aneurysm (AAA)., Methods: Summary statistics of telomere length and AAA were derived from IEU open genome-wide association studies and FinnGen R9, respectively. Bi-directional Mendelian randomization (MR) analysis was conducted to reveal the causal relationship between AAA and telomere length. Three transcriptome datasets were retrieved from the Gene Expression Omnibus database and telomere related genes was down-loaded from TelNet. The overlapping genes of AAA related differentially expressed genes (DEGs), module genes, and telomere related genes were used for further investigation. Telomere related diagnostic biomarkers of AAA were selected with machine learning algorisms and validated in datasets and murine AAA model. The correlation between biomarkers and immune infiltration landscape was established., Results: Telomere length was found to have a suggestive negative associations with AAA [IVW, OR 95%CI = 0.558 (0.317-0.701), P < 0.0001], while AAA showed no suggestive effect on telomere length [IVW, OR 95%CI = 0.997 (0.990-1.004), P = 0.4061]. A total of 40 genes was considered as telomere related DEGs of AAA. PLCH2, PRKCQ, and SMG1 were selected as biomarkers after multiple algorithms and validation. Immune infiltration analysis and single cell mRNA analysis revealed that PLCH2 and PRKCQ were mainly expressed on T cells, while SMG1 predominantly expressed on T cells, B cells, and monocytes. Murine AAA model experiments further validated the elevated expression of biomarkers., Conclusion: We found a suggestive effect of telomere length on AAA and revealed the potential biomarkers and immune mechanism of telomere length on AAA. This may shed new light for diagnosis and therapeutics on AAA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Xia and He.)

Immune cell infiltration is a significant pathological process in abdominal aortic aneurysms (AAA). T cells, particularly CD4 + T cells, are essential immune cells responsible for substantial infiltration of the aorta. Regulatory T cells (Tregs) in AAA have been identified as tissue-specific; however, the time, location, and mechanism of acquiring the tissue-specific phenotype are still unknown. Using single-cell RNA sequencing (scRNA-seq) on CD4 + T cells from the AAA aorta and spleen, we discovered heterogeneity among CD4 + T cells and identified activated, proliferating and developed aorta Tregs. These Tregs originate in the peripheral tissues and acquire the tissue-specific phenotype in the aorta. The identification of precursors for Tregs in AAA provides new insight into the pathogenesis of AAA., (© 2024 The Authors. Immunology published by John Wiley & Sons Ltd.)

Aortic aneurysms, particularly abdominal aortic aneurysms (AAAs), exhibit sex differences, with higher prevalence and severity in males than females, both in humans and experimental mouse models. In fact, male sex has been considered as the most potent nonmodifiable risk factor for AAA. Currently, there are no medications approved for the treatment of aortic aneurysms, despite the high lethality of ruptured aneurysms, which account for nearly 2% of all deaths. Moreover, the underlying molecular mechanisms mediating the sexual dimorphism of aortic aneurysms remain largely unknown. In this issue of the JCI, Mu et al. revealed a mechanism by which androgens, male sex hormones, exacerbate aortic aneurysms by suppressing programmed cell death protein 1 (PD-1) expression in T cells in an aldosterone and high salt-induced aortic aneurysm mouse model.

Background: Abdominal aortic aneurysm (AAA) development is driven by inflammation, in particular myeloid cells, which represent attractive biomarker candidates. Yet to date, the maximum aortic diameter is the only clinically applied predictor of AAA progression and indicator for surgical repair. We postulated that aortic inflammation is reflected in a systemic change of monocyte populations, which we investigated regarding marker potential in AAA diagnosis and prognosis., Methods: We conducted a single-center retrospective cohort study in a diagnostic setting, measuring monocyte subsets by flow cytometry in peripheral blood samples of 47 AAA patients under surveillance, matched with 25 healthy controls and 25 patients with peripheral artery disease (PAD). In a prognostic setting, we acquired longitudinal data of 60 AAA patients including aneurysm growth assessment by computed tomography at 6-month intervals., Results: Blood levels of total monocytes, CD16 + monocytes and particularly intermediate monocytes were significantly increased in AAA patients versus healthy individuals and were also elevated compared to PAD patients. The combination of intermediate monocyte and D-dimer blood levels outperformed the individual diagnostic marker values. Additionally, the elevated concentrations of total monocytes, intermediate monocytes, and monocyte-platelet aggregates (MPA) were suited to predict rapid AAA progression over short-term periods of six months. Of note, MPA were identified as independent predictor of AAA disease progression in multivariable analysis., Conclusion: Circulating monocyte subsets are elevated in AAA patients and support diagnosis and prediction of aneurysm progression. Monocyte subsets and D-dimer reflect different hallmarks (inflammation and hemostasis) of AAA pathology and when combined, may serve as improved biomarker., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Klopf, Zagrapan, Brandau, Lechenauer, Candussi, Rossi, Celem, Ziegler, Fuchs, Hayden, Krenn, Eilenberg, Neumayer and Brostjan.)

Background: Recent studies suggest that immune-mediated inflammation of perivascular adipose tissue of abdominal aortic aneurysms (AAAs) contributes to disease development and progression. Whether the perivascular adipose tissue of AAA is characterized by a specific adaptive immune signature remains unknown., Methods and Results: To investigate this hypothesis, we sequenced the T-cell receptor β-chain in the perivascular adipose tissue of patients with AAA and compared it with patients with aortic occlusive disease, who share the former anatomical site of the lesion and risk factors but differ in pathogenic mechanisms. Our results demonstrate that patients with AAA have a lower repertoire diversity than those with aortic occlusive disease and significant differences in variable/joining gene segment usage. Furthermore, we identified a set of 7 public T-cell receptor β-chain clonotypes that distinguished AAA and aortic occlusive disease with very high accuracy. We also found that the T-cell receptor β-chain repertoire differentially characterizes small and large AAAs (aortic diameter<55 mm and ≥55 mm, respectively)., Conclusions: This work supports the hypothesis that T cell-mediated immunity is fundamental in AAA pathogenesis and opens up new clinical perspectives.

Although there is an association between abdominal aortic aneurysm (AAA) and circulating immune cell phenotypes, the exact causal relationship remains unclear. This study aimed to explore the causal relationships between immune cell phenotypes and AAA risk using a bidirectional two-sample Mendelian randomization approach. Data from genome-wide association studies pertaining to 731 immune cell traits and AAA were systematically analyzed. Using strict selection criteria, we identified 339 immune traits that are associated with at least 3 single nucleotide polymorphisms. A comprehensive MR analysis was conducted using several methods including Inverse Variance Weighted, Weighted Median Estimator, MR-Egger regression, Weighted Mode, and Simple Median methods. CD24 on switched memory cells (OR = 0.922, 95% CI 0.914-0.929, P = 2.62e-79) at the median fluorescence intensities level, and SSC-A on HLA-DR + natural killer cells (OR = 0.873, 95% CI 0.861-0.885, P = 8.96e-81) at the morphological parameter level, exhibited the strongest causal associations with AAA. In the reverse analysis, no significant causal effects of AAA on immune traits were found. The study elucidates the causal involvement of multiple circulating immune cell phenotypes in AAA development, signifying their potential as diagnostic markers or therapeutic targets. These identified immune traits may be crucial in modulating AAA-related inflammatory pathways., (© 2024. The Author(s).)

Objectives: The causal association between immune cell traits and aortic aneurysm remains unknown., Methods: We performed a bidirectional two-sample Mendelian randomization analysis to explore the causality between 731 immune cell characteristics and the risk of abdominal aortic aneurysm and thoracic aortic aneurysms through publicly available genetic data, respectively. To examine heterogeneity and horizontal pleiotropy, Cochran's Q test and MR-Egger intercept were utilized. Additionally, multivariable Mendelian randomization analysis and meta-analysis were performed in further analysis., Results: We found that 20 immune phenotypes had a suggestive causality on abdominal aortic aneurysm, and 15 immune phenotypes had a suggestive causal effect on thoracic aortic aneurysm. After further false discovery rate adjustment (q value <0.1), CD20 on IgD+ CD38- B cell (q = 0.053) and CD127 on CD28+ CD4+ T cell (q = 0.096) were associated with an increased risk of abdominal aortic aneurysm, respectively, indicating a significant causality between them. After adjusting for smoking, there is still statistical significance between CD127 on CD28+ CD4+ T cell and abdominal aortic aneurysm. However, after adjusting for lipids, no statistical significance can be observed between CD127 on CD28+ CD4+ T cells and abdominal aortic aneurysm. Furthermore, there is still statistical significance between CD20 on IgD+ CD38- B cells and abdominal aortic aneurysm after adjusting for lipids and smoking, which was further identified by meta-analysis., Conclusions: We found a causal association between immune cell traits and aortic aneurysm by genetic methods, thus providing new avenues for future mechanism studies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Development of abdominal aortic aneurysms (AAA) enhances lesion group-2 innate lymphoid cell (ILC2) accumulation and blood IL5. ILC2 deficiency in Rora fl/fl Il7r Cre/+ mice or induced ILC2 depletion in Icos fl-DTR-fl/+ Cd4 Cre/+ mice expedites AAA growth, increases lesion inflammation, but leads to systemic IL5 and eosinophil (EOS) deficiency. Mechanistic studies show that ILC2 protect mice from AAA formation via IL5 and EOS. IL5 or ILC2 from wild-type (WT) mice, but not ILC2 from Il5 -/- mice induces EOS differentiation in bone-marrow cells from Rora fl/fl Il7r Cre/+ mice. IL5, IL13, and EOS or ILC2 from WT mice, but not ILC2 from Il5 -/- and Il13 -/- mice block SMC apoptosis and promote SMC proliferation. EOS but not ILC2 from WT or Il5 -/- mice block endothelial cell (EC) adhesion molecule expression, angiogenesis, dendritic cell differentiation, and Ly6C hi monocyte polarization. Reconstitution of WT EOS and ILC2 but not Il5 -/- ILC2 slows AAA growth in Rora fl/fl Il7r Cre/+ mice by increasing systemic EOS. Besides regulating SMC pathobiology, ILC2 play an indirect role in AAA protection via the IL5 and EOS mechanism., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Hexarelin, a synthetic growth hormone-releasing peptide, is shown to be protective in cardiovascular diseases such as myocardial infraction and atherosclerosis. However, the functional role of hexarelin in abdominal aortic aneurysm (AAA) remains undefined. The present study determined the effect of hexarelin administration (200 μg/kg twice per day) in a mouse model of elastase-induced abdominal aortic aneurysm. Echocardiography and in situ pictures showed hexarelin decreased infrarenal aorta diameter. Histology staining showed elastin degradation was improved in hexarelin-treated group. Hexarelin rescued smooth muscle cell contractile phenotype with increased α-SMA and decreased MMP2. Furthermore, hexarelin inhibited inflammatory cell infiltration, NLRP3 inflammasome activation and IL-18 production. Particularly, hexarelin suppressed NF-κB signaling pathway which is a key initiator of inflammatory response. These results demonstrated that hexarelin attenuated AAA development by inhibiting SMC phenotype switch and NF-κB signaling mediated inflammatory response., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Chronic Q fever is a zoonosis caused by the bacterium Coxiella burnetii which can manifest as infection of an abdominal aortic aneurysm (AAA). Antibiotic therapy often fails, resulting in severe morbidity and high mortality. Whereas previous studies have focused on inflammatory processes in blood, the aim of this study was to investigate local inflammation in aortic tissue., Methods: Multiplex immunohistochemistry was used to investigate local inflammation in Q fever AAAs compared to atherosclerotic AAAs in aorta tissue specimen. Two six-plex panels were used to study both the innate and adaptive immune systems., Results: Q fever AAAs and atherosclerotic AAAs contained similar numbers of CD68 + macrophages and CD3 + T cells. However, in Q fever AAAs, the number of CD68 + CD206 + M2 macrophages was increased, while expression of GM-CSF was decreased compared to atherosclerotic AAAs. Furthermore, Q fever AAAs showed an increase in both the number of CD8 + cytotoxic T cells and CD3 + CD8 - FoxP3 + regulatory T cells. Finally, Q fever AAAs did not contain any well-defined granulomas., Conclusions: These findings demonstrate that despite the presence of pro-inflammatory effector cells, persistent local infection with C. burnetii is associated with an immune-suppressed microenvironment., Funding: This work was supported by SCAN consortium: European Research Area - CardioVascualar Diseases (ERA-CVD) grant [JTC2017-044] and TTW-NWO open technology grant [STW-14716]., Competing Interests: KC, AS, TS, MG, LV, AJ, PP, RV, PW, CB, MS, KH, Mv, JD, RV No competing interests declared, JV Senior editor, eLife, (© 2022, Cortenbach et al.)

Mortality remains high after emergency open surgery for a ruptured abdominal aortic aneurysm (RAAA). The aim of the present study was to assess, if intravenous (IV) Interferon (IFN) beta-1a improve survival after surgery by up-regulating Cluster of differentiation (CD73). This is a multi-center phase II double-blind, 2:1 randomized, parallel group comparison of the efficacy and safety of IV IFN beta-1a vs. placebo for the prevention of death after open surgery for an infra-renal RAAA. All study patients presented a confirmed infra-renal RAAA, survived the primary emergency surgery and were treated with IFN beta-1a (10 μg) or matching placebo for 6 days after surgery. Major exclusion criteria included fatal hemorrhagic shock, chronic renal replacement therapy, diagnosed liver cirrhosis, severe congestive heart failure, advanced malignant disease, primary attempt of endovascular aortic repair (EVAR), and per-operative suprarenal clamping over 30 min. Main outcome measure was all-cause mortality at day 30 (D30) from initial emergency aortic reconstruction. The study was pre-maturely stopped due to a reported drug-drug interaction and was left under-powered. Out of 40 randomized patients 38 were included in the outcome analyses (27 IFN beta-1a and 11 placebo). There was no statistically significant difference between treatment groups at baseline except more open-abdomen and intestinal ischemia was present in the IFN beta-1a arm. D30 all-cause mortality was 22.2% (6/27) in the IFN beta-1a arm and 18.2% (2/11) in the placebo arm (OR 1.30; 95% CI 0.21-8.19). The most common adverse event relating to the IFN beta-1a was pyrexia (20.7% in the IFN beta-1a arm vs. 9.1% in the placebo arm). Patients with high level of serum CD73 associated with survival (P = 0.001) whereas the use of glucocorticoids and the presence of IFN beta-1a neutralizing antibodies associated with a poor CD73 response and survival. The initial aim of the trial, if postoperative INF beta-1a treatment results on better RAAA survival, could not be demonstrated. Nonetheless the anticipated target mechanism up-regulation of CD73 was associated with 100% survival. According to present results the INF beta-1a induced up-regulation of serum CD73 was blocked with both use of glucocorticoids and serum IFN beta-1a neutralizing antibodies. The study was pre-maturely stopped due to interim analysis after a study concerning the use if IV IFN beta-1a in ARDS suggested that the concomitant use of glucocorticoids and IFN beta-1a block the CD73 induction. Trial registration: ClinicalTrials.gov NCT03119701. Registered 19/04/2017 (retrospectively registered)., (© 2022. The Author(s).)

Background: Dapagliflozin, a sodium glucose transporter protein-2 (SGLT-2) inhibitor, reduces the risk for cardiovascular diseases. However, the influence of dapagliflozin on nondissecting abdominal aortic aneurysms (AAAs) remains unclear., Methods: AAAs were created in male C57BL/6 mice via intra-aortic porcine pancreatic elastase (PPE) infusion. Mice were daily treated with dapagliflozin (1 or 5 mg/kg body weight) or an equal volume of vehicle through oral gavage beginning one day prior to PPE infusion for 14 days. To investigate its translational value, dapagliflozin or vehicle was also administered to mice with existing AAAs in another cohort. Aortic diameters were measured prior to (day 0 for baseline) and 14 days after PPE infusion. After sacrifice, mice aortae were collected, and following histological analyses were performed., Results: Dapagliflozin treatment significantly reduced aneurysmal aortic expansion following PPE infusion as compared to vehicle treatment especially at 5 mg/kg body weight (approximately 21% and 33% decreases in 1 and 5 mg/kg treatment groups, respectively). The dose-dependent attenuation of AAAs by dapagliflozin was also confirmed on histological analyses. Dapagliflozin remarkably reduced aortic accumulation of macrophages, CD4 + T cells, and B cells particularly following dapagliflozin treatment at 5 mg/kg. Dapagliflozin treatment also markedly attenuated medial SMC loss. Though the difference was not significant, dapagliflozin treatment tended to attenuate CD8 + T cells and elastin degradation. Dapagliflozin treatment at 5 mg/kg caused a 53% reduction in neovessel density. Furthermore, dapagliflozin treatment mitigated further progress of existing AAAs., Conclusion: Dapagliflozin treatment ameliorated PPE-induced AAAs by inhibiting aortic leukocytes infiltration and angiogenesis., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2022 Haole Liu et al.)

B cell-activating factor (BAFF), part of a tumor necrosis factor family of cytokines, was recently identified as a regulator of atherosclerosis; however, its role in aortic aneurysm has not been determined. Here, the study examined the effect of selective BAFF antagonism using an anti-BAFF antibody (blocks binding of BAFF to receptors BAFF receptor 3, transmembrane activator and CAML interactor, and B-cell maturation antigen) and mBaffR-mFc (blocks binding of BAFF to BAFF receptor 3) on a murine model of abdominal aortic aneurysm (AAA). In a prevention strategy, the antagonists were injected before the induction of AAA, and in an intervention strategy, the antagonists were injected after the induction of AAA. Both strategies attenuated the formation of AAA. In the intervention group, BAFF antagonism depleted most of the mature B-cell subsets in spleen and circulation, leading to enhanced resolution of inflammation in AAA as indicated by decreased infiltration of B cells and proinflammatory macrophages and a reduced number of apoptotic cells. In AAA tissues, B cells and macrophages were found in close contact. In vitro, B cells, irrespective of treatment with BAFF, impaired the efferocytosis activity of macrophages, suggesting a direct innate role of B cells on macrophage function. Altogether, BAFF antagonism affects survival of the mature B cells, promotes resolution of inflammation in the aorta, and attenuates the growth of AAA in mice., (Copyright © 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: Elastase-induced abdominal aortic aneurysm (AAA) model is widely used for aneurysmal pathogenesis and translational research. However, temporal alternations in aneurysmal histologies remain unknown. This study is aimed at analyzing temporal immunopathologies of aneurysmal aorta following experimental AAA induction., Methods: Male C57BL/6J mice at the age of 10-14 weeks received intra-aortic infusion of elastase to induce AAAs. Aortic diameters at the baseline and indicated days after AAA induction were measured, and aortae were collected for histopathological analysis., Results: Aorta diameters increased from 0.52 mm at the baseline levels to 0.99 mm, 1.34 mm, and 1.41 mm at days 7, 14, and 28, respectively, corresponding 90%, 158%, and 171% increases over the baseline level. Average aortic diameters did not differ between days 14 and 28. Severe elastin degradation and smooth muscle cell depletion were found at days 14 and 28 as compared to the baseline and day 7. No difference in the scores of medial elastin and SMC destruction was noted between days 14 and 28. Consistent results were found for leukocyte accumulation, neoangiogenesis, and matrix metalloproteinase expression. Twenty-eight days after AAA induction, all aneurysmal pathologies showed an attenuated trend, although most histopathological parameters did no differ between days 14 and 28., Conclusion: Our data suggest that almost aneurysmal immunohistopathologies reach maximal 14 days following AAA induction. Analysis of day 14 histologies is sufficient for AAA pathogenesis and translational studies in elastase-induced mouse experimental AAAs., Competing Interests: The authors declared no conflict of interest., (Copyright © 2021 Kangli Tian et al.)

Objective: An Abdominal aortic aneurysm (AAA), a deadly disease in elderly population, is featured by expansion of aortic diameter, degradation and weakening of vasculature. Its common and significant characteristics are disarray and inflammation in vasculature. We tested the hypothesis that the reversal of abdominal aortic aneurysm by pentagalloyl glucose-loaded nanoparticles (PGG-NPs) therapy that targets degraded elastin suppresses inflammatory and immune markers to ameliorate the pathophysiology of the disease in advance stage aneurysm in a porcine pancreatic elastase (PPE)-induced mouse model of AAA., Methods and Results: After induction of aneurysm in pathogen-free C57BL/6 male mice by applying PPE peri-adventitially to the abdominal aorta, once a week for two doses of intravenous injections of pentagalloyl glucose-loaded nanoparticles (PGG-NPs) conjugated with elastin targeted antibody were used to reverse the aneurysms. We showed that PGG-NPs therapy could suppress infiltration of macrophages, CD8 and CD4 subsets of T cells, matrix metalloproteinases (MMPs), inflammatory cytokines interferon (IFN-γ) and interleukin (IL)-6 at the local and systemic level. Moreover, such PGG-NPs therapy increases the induction of anti-inflammatory cytokines IL-13, IL-27 and IL-10 at the local and systemic level. The therapy also led to remodeling of elastic lamina at the aneurysm site., Conclusion: Nanoparticles-loaded pentagalloyl glucose therapy can be an effective treatment option against advanced stage aneurysms to reverse the disease by ameliorating inflammation and restoring arterial homeostasis., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Abdominal aortic aneurysm (AAA) is a chronic inflammatory disease characterized by localized progressive dilatation. Currently, paeonol has been shown to possess anti-inflammatory and protective cardiovascular properties. Our study aimed to investigate the potential influences of paeonol on AAA progression., Methods: Experimental AAAs were created in C57BL/6J mice by intra-aortic infusion of porcine pancreatic elastase, and then intragastrically administered paeonol (20 mg/kg/day) for 14 days. The effects of paeonol on experimental AAA were measured by ultrasound imaging, histopathology, and western blot analyses., Results: Paeonol treatment limited the enlargement of the aneurysmal diameter and alleviated the depletion of elastic fibers and vascular smooth muscle cells (VSMCs). Furthermore, the infiltration of CD68+ macrophages and CD8+ lymphocytes was obviously attenuated after paeonol administration, along with mural neoangiogenesis. Western blot results showed that paeonol inhibited the expression of matrix metalloproteinase (MMP) and the NF-κB pathway activation., Conclusions: Paeonol might prevent experimental AAA progression by inhibiting the NF-κB pathway, which suggests that it is a potential drug for AAA., (Copyright © 2021. Published by Elsevier Inc.)

Aortic diseases are the primary public health concern. As asymptomatic diseases, abdominal aortic aneurysm (AAA) and atherosclerosis are associated with high morbidity and mortality. The inflammatory process constitutes an essential part of a pathogenic cascade of aortic diseases, including atherosclerosis and aortic aneurysms. Inflammation on various vascular beds, including endothelium, smooth muscle cell proliferation and migration, and inflammatory cell infiltration (monocytes, macrophages, neutrophils, etc.), play critical roles in the initiation and progression of aortic diseases. The tryptophan (Trp) metabolism or kynurenine pathway (KP) is the primary way of degrading Trp in most mammalian cells, disturbed by cytokines under various stress. KP generates several bioactive catabolites, such as kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykynurenine (3-HK), etc. Depends on the cell types, these metabolites can elicit both hyper- and anti-inflammatory effects. Accumulating evidence obtained from various animal disease models indicates that KP contributes to the inflammatory process during the development of vascular disease, notably atherosclerosis and aneurysm development. This review outlines current insights into how perturbed Trp metabolism instigates aortic inflammation and aortic disease phenotypes. We also briefly highlight how targeting Trp metabolic pathways should be considered for treating aortic diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ramprasath, Han, Zhang, Yu and Zou.)

OBJECTIVE: Leukocytes contribute to the development of abdominal aortic aneurysm (AAA). We evaluated whether associations of differential leukocyte counts with AAA persist after accounting for traditional risk factors of AAA. APPROACH AND RESULTS: Among 11 217 adults from the Atherosclerosis Risk in Communities Study, we evaluated associations of differential leukocyte counts at baseline (1987–1989) with incident AAAs over a median follow-up of 22.5 years, using Cox proportional hazards regression. Each differential leukocyte count was categorized into 5 groups—below normal, tertiles within the normal range, and above normal, with the first tertile serving as the referent. We identified 377 incident AAAs through 2011, using hospital discharge diagnoses, linked Medicare records, or death certificates. At baseline, higher neutrophil, monocyte, and eosinophil counts were associated with higher risk of AAA, independent of smoking, other differential leukocyte counts, and other traditional risk factors. The association with incident AAA was the strongest for above normal neutrophil count, with an adjusted hazard ratio (95% CI) of 2.17 (1.29–3.64). Below normal neutrophil, lymphocyte, eosinophil and basophil counts were associated with higher risk of AAA with adjusted hazard ratio (95% CI) between 1.86 (1.04–3.35) and 1.62 (1.10–2.39). CONCLUSIONS: Higher neutrophil, monocyte, and eosinophil counts in midlife are associated with higher risk of AAA, even after accounting for traditional risk factors such as smoking, obesity, and atherosclerosis. This suggests the need to identify nontraditional risk factors and treatment strategies to mitigate the residual risk of AAA conferred by midlife inflammation. Whether immunosuppression is associated with higher risk of AAA needs further investigation.

Abdominal aortic aneurysm (AAA) is characterized by inflammatory cell infiltration and aggravated by hyperhomocysteinemia (HHcy). It is unknown whether the homocysteine (Hcy)-activated RNA methyltransferase NOP2/Sun domain family member 2 (NSun2) is associated with AAA. Here, we found that NSun2 deficiency significantly attenuated elastase-induced and HHcy-aggravated murine AAA with decreased T cell infiltration in the vessel walls. T cell labeling and adoptive transfer experiments confirmed that NSun2 deficiency inhibited the chemotaxis of vessels to T cells. RNA sequencing of endothelial cells showed that Hcy induced the accumulation of various metabolic enzymes of the phospholipid PC-LPC-LPA metabolic pathway, especially autotaxin (ATX). In the elastase-induced mouse model of AAA, ATX was specifically expressed in the endothelium and the plasma ATX concentration was upregulated and even higher in the HHcy group, which were decreased dramatically by NSun2 knockdown. In vitro Transwell experiments showed that ATX dose-dependently promoted T cell migration. HHcy may upregulate endothelial ATX expression and secretion and in turn recruit T cells into the vessel walls to induce vascular inflammation and consequently accelerate the pathogenesis of AAA. Mechanistically, secreted ATX interacted with T cells by binding to integrin α4, which subsequently activated downstream FAK/Src-RhoA signaling pathways and then induced T cell chemokinesis and adhesion. ATX overexpression in the vessel walls reversed the inhibited development of AAA in the NSun2-deficient mice. Therefore, NSun2 mediates the development of HHcy-aggravated AAA primarily by increasing endothelial ATX expression, secretion and T cell migration, which is a novel mechanism for HHcy-aggravated vascular inflammation and pathogenesis of AAA.

Regarding the role of micro RNAs (miRNA) in the proliferation and differentiation of T cells as well as the controversy around the role of bacteria in the pathogenesis of abdominal aortic aneurysm (AAA), the effects of Helicobacter pylori (Hp) and Lactobacillus acidophilus (La) were investigated in the induction of miRNAs and apoptosis in CD4+ memory T (Tem) cells of AAA patients and controls. Signature atherosclerosis miRNAs 21, 92a, 146a, 155, 326 and 663 were measured in the sera and tissues of AAA patients and control. PBMCs separately and in co-culture with HUVEC were treated with Hp-water-extract (HpWE) and La-conditioned-medium (LaCM). Apoptosis and miRNA levels were assessed in the isolated Tem by flowcytometry and real-time-PCR. In single-culture, HpWE increased apoptosis and miR-155 and LaCM decreased apoptosis and increased miR-21. In co-culture, apoptosis decreased in both groups in response to CagA+HpWE. Also, all miRNAs increased in patients Tem but in controls, only miR- 146a and 21 showed changes. Although, apoptosis was similar in Tem of patients and controls, the effects of Hp and La were different on the induction of apoptosis and miRNAs and also these bacteria showed different impacts in single and co-culture conditions. Beyond the direct effects of these bacteria on the pathogenesis of diseases, their effects on miRNAs expression may shed light on their roles in the development and the prevention of AAA., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Macrophages contribute to abdominal aortic aneurysm (AAA), but the effect of macrophage on AAA formation is not totally understood. Recent research proved that macrophage pyroptosis plays an important role in many cardiovascular disease. However, whether macrophage pyroptosis is involved in AAA and its mechanism remains unknown. In this study, we found that the pyroptosis significantly increased in AAA tissues. β5i inhibitor PR-957 treatment or β5i deficiency markedly ameliorated AAA formation and decreased the pyroptosis. Pyroptosis were also significantly attenuated in bone marrow derived macrophages (BMDM) from β5i -/- mice compared with the control group when they were subjected to OXLDL. Mechanistically, β5i may promote activation of NFκB which augment NLRP3 expression. In conclusion, this study suggested macrophages pyroptosis are involved in AAA and inhibition or knockout of β5i decreased macrophage pyroptosis via IκB/NFκB pathway., Competing Interests: Declaration of competing interest The authors confirm that there are no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

There is no proven medical therapy to inhibit the progression of abdominal aortic aneurysm (AAA) in the clinical setting. To develop a novel therapeutic approach for the treatment of AAA, we focused on vaccination targeting Ang II (angiotensin II) and assessed the effect of an Ang II peptide vaccine on the progression of AAA using a rat model. Ang II peptide was conjugated with KLH (keyhole limpet hemocyanin) carrier protein to induce a sufficient immune response. Male rats were subcutaneously immunized with Ang II-KLH with an adjuvant on days 0, 14, and 28. Aortic dilatation was induced by intraluminal incubation with elastase on day 35. Treatment with Ang II vaccine successfully induced the production of a high titer of anti-Ang II antibodies. Immunization with Ang II vaccine resulted in a significant reduction in expansion of the aortic diameter compared with control rats, without a blood pressure-lowering effect. Four weeks after operation, the increase in Ang II in the aneurysm wall was significantly inhibited by treatment with Ang II vaccine. Inhibition of Ang II action led to suppression of the inflammatory response in the AAA wall through attenuation of the NFκB (nuclear factor kappa B) and c-jun N-terminal kinase signaling cascades. Treatment with Ang II vaccine inhibited accumulation of macrophages in the AAA wall. In addition, expression of TNF-α (tumor necrosis factor alpha) and activation of MMP (matrix metalloproteinase)-2 and MMP-9 were also inhibited by treatment with Ang II vaccine, resulting in protection against the destruction of elastic fibers. This vaccine therapy could become a potent therapeutic option to treat patients with AAA.

Inflammatory mediators such as cytokines and chemokines are crucially involved in the development of abdominal aortic aneurysm (AAA). Here we report that CaCl 2 application into abdominal aorta induces AAA with intra-aortic infiltration of macrophages as well as enhanced expression of chemokine (C-C motif) ligand 3 (CCL3) and MMP-9. Moreover, infiltrating macrophages express C-C chemokine receptor 5 (CCR5, a specific receptor for CCL3) and MMP-9. Both Ccl3 -/- mice and Ccr5 -/- but not Ccr1 -/- mice exhibit exaggerated CaCl 2 -inducced AAA with augmented macrophage infiltration and MMP-9 expression. Similar observations are also obtained on an angiotensin II-induced AAA model. Immunoneutralization of CCL3 mimics the phenotypes observed in CaCl 2 -treated Ccl3 -/- mice. On the contrary, CCL3 treatment attenuates CaCl 2 -induced AAA in both wild-type and Ccl3 -/- mice. Consistently, we find that the CCL3-CCR5 axis suppresses PMA-induced enhancement of MMP-9 expression in macrophages. Thus, CCL3 can be effective to prevent the development of CaCl 2 -induced AAA by suppressing MMP-9 expression.

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease with an up to 80% mortality in case of rupture. Current biomarkers fail to account for size-independent risk of rupture. By combining the information of different molecular probes, multi-target molecular MRI holds the potential to enable individual characterization of AAA. In this experimental study, we aimed to examine the feasibility of simultaneous imaging of extracellular collagen and inflammation for size-independent prediction of risk of rupture in murine AAA. The study design consisted of: (1) A outcome-based longitudinal study with imaging performed once after one week with follow-up and death as the end-point for assessment of rupture risk. (2) A week-by-week study for the characterization of AAA development with imaging after 1, 2, 3 and 4 weeks. For both studies, the animals were administered a type 1 collagen-targeted gadolinium-based probe (surrogate marker for extracellular matrix (ECM) remodeling) and an iron oxide-based probe (surrogate marker for inflammatory activity), in one imaging session. In vivo measurements of collagen and iron oxide probes showed a significant correlation with ex vivo histology (p < 0.001) and also corresponded well to inductively-coupled plasma-mass spectrometry and laser-ablation inductively-coupled plasma mass spectrometry. Combined evaluation of collagen-related ECM remodeling and inflammatory activity was the most accurate predictor for AAA rupture (sensitivity 80%, specificity 100%, area under the curve 0.85), being superior to information from the individual probes alone. Our study supports the feasibility of a simultaneous assessment of collagen-related extracellular matrix remodeling and inflammatory activity in a murine model of AAA.

Aims: Overactivated B cells secrete pathological antibodies, which in turn accelerate the formation of abdominal aortic aneurysms (AAAs). Hyperhomocysteinaemia (HHcy) aggravates AAA in mice; however, the underlying mechanisms remain largely elusive. In this study, we further investigated whether homocysteine (Hcy)-activated B cells produce antigen-specific antibodies that ultimately contribute to AAA formation., Methods and Results: ELISA assays showed that HHcy induced the secretion of anti-beta 2 glycoprotein I (anti-β2GPI) antibody from B cells both in vitro and in vivo. Mechanistically, Hcy increased the accumulation of various lipid metabolites in B cells tested by liquid chromatography-tandem mass spectrometry, which contributed to elevated anti-β2GPI IgG secretion. By using the toll-like receptor 4 (TLR4)-specific inhibitor TAK-242 or TLR4-deficient macrophages, we found that culture supernatants from Hcy-activated B cells and HHcy plasma IgG polarized inflammatory macrophages in a TLR4-dependent manner. In addition, HHcy markedly increased the incidence of elastase- and CaPO4-induced AAA in male BALB/c mice, which was prevented in μMT mice. To further determine the importance of IgG in HHcy-aggravated AAA formation, we purified plasma IgG from HHcy or control mice and then transferred the IgG into μMT mice, which were subsequently subjected to elastase- or CaPO4-induced AAA. Compared with μMT mice that received plasma IgG from control mice, μMT mice that received HHcy plasma IgG developed significantly exacerbated elastase- or CaPO4-induced AAA accompanied by increased elastin degradation, MMP2/9 expression, and anti-β2GPI IgG deposition in vascular lesions, as shown by immunofluorescence histochemical staining., Conclusion: Our findings reveal a novel mechanism by which Hcy-induced B cell-derived pathogenic anti-β2GPI IgG might, at least in part, contribute to HHcy-aggravated chronic vascular inflammation and AAA formation., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Objective: Abdominal aortic aneurysm (AAA) is a chronic inflammatory disease. Studies of human aneurysm tissue demonstrate dense inflammatory cell infiltrates with CD4 + T cells predominating. Regulatory T cells (Tregs) play an important role in inhibiting pro-inflammatory T cell proliferation, therefore, limiting collateral tissue destruction. The aim of this study was to investigate whether ex vivo augmentation of human Tregs attenuates aneurysm formation in humanized murine model of AAA., Methods: Circulating Treg population in AAA patients and age- and gender-matched controls were determined by real-time polymerase chain reaction and flow cytometry. To create humanized murine model of AAA, irradiated Rag1-deficient (Rag1 -/- ) mice, without mature T lymphocytes, at 7 weeks of age were given 5 × 10 6 of human CD4 + T cells intraperitoneally. Then the mice underwent CaCl 2 aneurysm induction. Aortic diameters were measured before and at 6 weeks after aneurysm induction. Aortic tissue was collected for histology and protein extraction. Verhoeff-Van Gieson stain was used for staining elastic fiber. CD4 + T cells in the aortic tissue were detected by immunohistochemical staining., Results: In human peripheral blood mononuclear cells, the proportion of Tregs are decreased in AAA patients compared with matched control patients with significant vascular disease. We first validated the role of Tregs in the CaCl 2 model of AAA. To determine the role of human T cells in AAA formation, Rag1 -/- mice, resistant to CaCl 2 -aneurysm induction, were transplanted with human CD4 + T cells. Human CD4 + T cells were able to drive aneurysm formation in Rag1 -/- mice. We show that ex vivo augmentation of human Tregs by interleukin-2 resulted in decreased aneurysm progression., Conclusions: These data suggest that the ex vivo expansion of human Tregs may be a potential therapeutic strategy for inhibiting progression of AAA., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Abdominal aortic aneurysms (AAAs) are currently one of the leading causes of death in developed countries. Inflammation is crucial in the disease progression, having a substantial impact on various determinants in AAAs development. Magnetic particle imaging (MPI) is an innovative imaging modality, enabling the highly sensitive detection of magnetic nanoparticles (MNPs), suitable as surrogate marker for molecular targeting of vascular inflammation. For this study, Apolipoprotein E-deficient-mice underwent surgical implantation of osmotic minipumps with constant Angiotensin II infusion. After 3 and 4 weeks respectively, in-vivo-magnetic resonance imaging (MRI), ex-vivo-MPI and ex-vivo-magnetic particle spectroscopy (MPS) were performed. The results were validated by histological analysis, immunohistology and laser ablation-inductively coupled plasma-mass spectrometry. MR-angiography enabled the visualization of aneurysmal development and dilatation in the experimental group. A close correlation (R = 0.87) with histological area assessment was measured. Ex-vivo-MPS revealed abundant iron deposits in AAA samples and ex-vivo histopathology measurements were in good agreement (R = 0.76). Ex-vivo-MPI and MPS results correlated greatly (R = 0.99). CD68-immunohistology stain and Perls'-Prussian-Blue-stain confirmed the colocalization of macrophages and MNPs. This study demonstrates the feasibility of ex-vivo-MPI for detecting inflammation in AAA. The quantitative ability for mapping MNPs establishes MPI as a promising tool for monitoring inflammatory progression in AAA in an experimental setting.

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is an enzyme that detoxifies aldehydes by converting them to carboxylic acids. ALDH2 deficiency is known to increase oxidative stress. Increased oxidative stress plays a pivotal role in abdominal aortic aneurysm (AAA) pathogenesis. Reactive oxygen species (ROS) promote degradation of the extracellular matrix (ECM) and vascular smooth muscle cell (VSMC) apoptosis. Reducing oxidative stress by an ALDH2 activator could have therapeutic potential for limiting AAA development. We hypothesized that ALDH2 deficiency could increase the risk for AAA by decreasing ROS elimination and that an ALDH2 activator could provide an alternative option for AAA treatment. The National Center for Biotechnology (NCBI) Gene Expression Omnibus (GEO) database was used. Human aortic smooth muscle cells (HASMCs) were used for the in vitro experiments. Gene-targeted ALDH2*2 KI knock-in mice on a C57BL/6J background and apolipoprotein E knockout (ApoE KO) mice were obtained. An animal model of AAA was constructed using osmotic minipumps to deliver 1000 ng/kg/min angiotensin II (AngII) for 28 days. Patients with AAA had significantly lower ALDH2 expression levels than normal subjects. ALDH2*2 KI mice were susceptible to AngII administration, exhibiting significantly increased AAA incidence rates and increased aortic diameters. Alda-1, an ALDH2 activator, reduced AngII-induced ROS production, NF-kB activation, and apoptosis in HASMCs. Alda-1 attenuated AngII-induced aneurysm formation and decreased aortic expansion in ApoE KO mice. We concluded that ALDH2 deficiency is associated with the development of AAAs in humans and a murine disease model. ALDH2 deficiency increases susceptibility to AngII-induced AAA formation by attenuating anti-ROS effects and increasing VSMC apoptosis and vascular inflammation. Alda-1 was shown to attenuate the progression of experimental AAA in a murine model., (© 2020 Federation of American Societies for Experimental Biology.)

Abdominal aortic aneurysm (AAA) is a degenerative inflammatory disease with unknown etiology. AAA is characterized by abdominal aortic dilatation more than 3 cm and is often asymptomatic, but the rupture of aneurysm can lead to death. Age, smoking and male sex are major predisposing factors of AAA. This study compares the effect of Helicobacter (H.) pylori and Lactobacillus (L.) acidophilus on the cytokine profile of PBMCs of 5 men with abdominal aortic aneurysm (AAA) and 5 men with normal/insignificant angiography, CT-Scan and ultrasonography results in the single-culture and in the co-culture with HUVECs. IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-17A, IL-17 F, IL-21, IL-22, IFN-γ and TNF-α were measured in culture supernatants using a commercial fluorescent-labeled-bead assay. In general, CagA+ H. pylori-extract induced higher production of IFN-γ, IL-13 and IL-21 by PBMCs. Treatment of patients' PBMCs with CagA + H. pylori-extract induced Th2 cytokines while treatment of controls' PBMCs with CagA + H. pylori-extract increased Th1 cytokines. In the co-culture, however, patients' PBMCs produced Th1 cytokines irrespective of extract treatment, while controls' PBMCs produced Th2 cytokines and decreased IL-10. CagA+ H. pylori- as well as L. acidophilus-extract induced higher levels of IL-9 by controls' PBMCs in co-culture with HUVECs than patients (P = 0.05 and P = 0.01). The cytokine pattern of PBMCs induced by CagA+ H. pylori- and L. acidophilus-extracts in the co-culture with HUVECs shows differences in AAA patients and in comparison to controls. Decreased secretion of IL-9, IL-21 and IL-22 by PBMCs of patients treated with CagA+ H. pylori extract in co-culture, as opposed to non-AAA controls may indicate the active role ECs play in AAA. Simultaneous production of IL-10 and Th1 cytokines in patients and pronounced Th2 cytokines in controls in response to both bacteria may point to the inherent differences between patients and controls, which need further investigation., Competing Interests: Declaration of Competing Interest The authors declare no competing interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aim: Inflammation plays a significant role in the pathogenesis of human abdominal aortic aneurysm (AAA). AEBP1 can promote activation of the NF-κB pathway, subsequently affecting the expression of NF-κB target genes, including inflammatory cytokines and matrix metalloproteinases (MMPs). Our objective was to examine the role of AEBP1 in the development of AAA and characterize the underlying mechanism., Methods: ITRAQ, RT-PCR, western blot, immunohistochemistry, and ELISA were used to compare different experimental groups with the controls and to determine the differentially expressed genes. We generated an AAA model using porcine pancreatic elastase in Sprague-Dawley rats and silenced their AEBP1 in vivo by adenoviruses injected intra-adventitially. We also silenced or overexpressed AEBP1 in human vascular smooth muscle cells in vitro in the presence and in the absence of NF-κB inhibitor BAY 11-7082., Results: Proteome iTRAQ revealed a high expression of AEBP1 in AAA patients, which was verified by qRT-PCR, western blot, immunohistochemistry, and ELISA. The mean expression level of AEBP1 in AAA patients was higher than that in controls. Along with AEBP1 upregulation, we also verified mis-activation of NF-κB in human AAA samples. The in vivo studies indicated that AEBP1 knockdown suppressed AAA progression. Finally, the in vitro studies illustrated that AEBP1 promotes activation of the NF-κB pathway, subsequently upregulating pro-inflammatory factors and MMPs., Conclusions: Our results indicate a role of AEBP1 in the pathogenesis of AAA and provide a novel insight into how AEBP1 causes the development of AAA by activating the NF-κB pathway.

Allergic asthma with high plasma IgE levels is a significant risk factor of human abdominal aortic aneurysm (AAA). This study tests a direct role of IgE in angiotensin-II (Ang-II) perfusion- and peri-aortic CaCl 2 injury-induced AAA in mice. In both models, IgE-deficiency in Apoe -/- Ige -/- mice blunts AAA growth and reduces lesion accumulation of macrophages, CD4 + and CD8 + T cells, and lesion MHC class-II expression, CD31 + microvessel growth, and media smooth muscle cell loss, compared with those from Apoe -/- control mice. Real time-PCR reveals significant reductions in expression of neutrophil chemoattractants MIP-2α and CXCL5 in AAA lesions or macrophages from Apoe -/- Ige -/- mice, along with reduced lesion Ly6G + neutrophil accumulation. Consistent with reduced lesion inflammatory cell accumulation, we find significant reductions of plasma and AAA lesion IL6 expression in Apoe -/- Ige -/- mice. Immunofluorescent staining and FACS analysis show that AAA lesion neutrophils express FcεR1. Mechanistic study demonstrates that IgE induces neutrophil FcεR1 expression, activates MAPK signaling, and promotes IL6 production. This study supports a direct role of IgE in AAA by promoting lesion chemokine expression, inflammatory cell accumulation, MAPK signaling, and cytokine expression. IgE inhibition may represent a novel therapeutic approach in AAA management., (© 2020 Federation of American Societies for Experimental Biology.)

Background: Abdominal aortic aneurysm (AAA) is a potentially life-threatening disease, and until today there is no other treatment available than surgical intervention. Dipeptidyl peptidase-4 (DPP4)-inhibitors, used clinically to treat type 2 diabetes, have in murine models been shown to attenuate aneurysm formation and decrease aortic wall matrix degradation, inflammation and apoptosis. Our aim was to investigate if DPP4 is present, active and differentially expressed in human AAA., Methods and Results: DPP4 gene expression was elevated in both media and adventitia of AAA tissue compared with control tissue, as measured by microarrays and qPCR, with consistent findings in external data. The plasma activity of DPP4 was however lower in male patients with AAA compared with age- and gender-matched controls, independently of comorbidity or medication. Immunohistochemical double staining revealed co-localization of DPP4 with cells positive for CD68, CD4 and -8, CD20, and SMA. Gene set enrichment analysis demonstrated that expression of DPP4 in AAA tissue correlated with expression of biological processes related to B- and T-cells, extracellular matrix turnover, peptidase activity, oxidative stress and angiogenesis whereas it correlated negatively with muscle-/actin-related processes., Conclusion: DPP4 is upregulated in both media and adventitia of human AAA and correlates with aneurysm pathophysiological processes. These results support previous murine mechanistic studies and implicate DPP4 as a target in AAA disease., Competing Interests: The authors have declared that no competing interests exist.

Introduction: CD4-positive T lymphocytes (CD4 cells) play a significant role in human abdominal aortic aneurysm (AAA). However, we know little about the role of the different CD4 subtypes., Objective: We aimed to discover the circulatory CD4 phenotypic marker profile and the roles of the newly found T helper cell 9 (Th9) and follicular helper T cells (Tfh) and that of inflammasomes in CD4 cells from AAA patients., Methods: We extracted CD4 cells from 30 AAA patients and 21 age-matched controls. Phenotype-specific transcription factors (TFs) and inflammasomes were analyzed with qRT-PCR., Results: Th17-, Th1-, Th9-, and Tfh-specific TFs and inflammasome components NLRP1 (NLR family pyrin domain-containing 1), NLRP3, NLRC4, AIM2 (absent in melanoma 2), PYCARD (apoptosis speck-like protein containing a CARD), and CASP1 (caspase 1) were upregulated, and T regulatory cell- and Th2-specific TFs were downregulated in the patients' peripheral blood CD4 cells. Homocysteine was involved in Tfh and Th17 imbalance by AIM2 and NLRP1 inflammasome upregulation. Blood total cholesterol level correlated positively with NLRP1 expression, and blood low-density lipoprotein level correlated negatively with FOXP3 expression., Conclusions: Inflammasome-induced CD4 cell imbalance was involved in AAA. We thought that AAA might be a consequence of synergism between systemic immune imbalance and local autoimmunity., (© 2020 S. Karger AG, Basel.)

Background: The pathogenesis of atherosclerotic abdominal aortic aneurysms (AAAs) remains not fully understood. Histological analyses confirm chronic adventitial and medial inflammatory cell infiltration, and its pathophysiology involves the upregulation of proteolytic pathways; added to this, genetic factors have been suggested to favor the susceptibility for AAA. The aim of the present study was to analyze the association between genetic polymorphism of the class II human leukocyte antigens (HLAs, HLA-DRB1) with the susceptibility to develop AAA in Mexican patients and to initiate a pilot study of single-nucleotide polymorphisms (SNPs) rs1024611 in the monocyte chemoattractant protein-1 (MCP-1/CCL2) gene to investigate a possible role in the AAA pathogenesis., Methods: In a cohort of patients with AAA, HLA molecular typing was completed for DRB1 loci with LABType SSO-One Lambda kit in 39 patients (69% men with a mean age of 72 years) and compared with 99 without the disease (60% men, mean age 65 years) (control group). Genotyping of rs1024611 in the MCP-1 gene was performed using TaqMan predesigned SNP genotyping assays in 27 patients with AAA (63% men, mean age of 71). Gene frequencies (gfs) and genotype frequencies (Gfs) were determined; categorical data were analyzed by nonparametric statistic test at significance level (P < 0.05), and odds ratios (ORs) were calculated using the STATA v14 software and StatCalc software Epi Info™ 7.2.2.2., Results: Seventy-eight HLA-DRB1 alleles of patients with AAA and 198 from the control group were studied. We observed that the gf of HLA-DRB1*01 was 0.128 in the AAA group compared with 0.05 in the control group (P = 0.03, OR: 2.6, 95% confidence interval [CI]: 1.04-6.5); the gf of HLA-DRB1*16 was 0.115 in the AAA and 0.025 in control group (P = 0.002, OR: 5, 95% CI: 1.6-16.9). The Gf for SNP rs1024611 were 0.51 in the GA genotype, 0.30 in AA, and 0.19 of GG. Four patients with the proinflammatory homozygous genotype GG (80%) were women and younger than patients with other genotypes, and only one had a history of dyslipidemia., Conclusions: The dissection and interpretation of an immunogenetic profile in patients with AAA is an active and complex field of research that might assist in a more precise identification of those patients at genetic risk. Our study demonstrated increased frequencies of HLA-DRB1*01 and HLA-DRB1*16 alleles in Mexican patients with AAA compared with an ethnically matched control group., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: The role of chronic inflammation in abdominal aortic aneurysm (AAA) is controversial. CD11c+ antigen-presenting cells (APCs) (dendritic cells (DCs)) have been reported in human AAA samples but their role is unclear. The effect of conditional depletion of CD11c+ cells on experimental AAA was investigated in the angiotensin II (AngII)-infused apolipoprotein E-deficient (ApoE-/-) mouse model., Approach: CD11c-diphtheria toxin (DT or D.tox) receptor (DTR), ovalbumin (OVA) fragment aa 140-386, and enhanced green fluorescent protein (eGFP)-ApoE-/- (CD11c.DOG.ApoE-/-) mice were generated and CD11c+ cell depletion achieved with D.tox injections (8 ng/g body weight, i.p., every-other-day). AAA formation and growth were assessed by measurement of supra-renal aortic (SRA) diameter in vivo by serial ultrasound and by morphometry assessment of harvested aortas at the end of the study., Results: Depletion of CD11c+ cells by administration of D.tox on alternative days was shown to reduce the maximum diameter of AAAs induced by 28 days AngII infusion compared with controls (D.tox, 1.58 ± 0.03 mm vs Vehicle control, 1.81 ± 0.06 mm, P<0.001). CD11c+ depletion commencing after AAA establishment by 14 days of AngII infusion, was also shown to lead to smaller AAAs than controls after a further 14 days (D.tox, 1.54 ± 0.04 mm vs Vehicle control, 1.80 ± 0.03 mm, P<0.001). Flow cytometry revealed significantly lower numbers of circulating CD44hi CD62Llo effector CD4 T cells, CD44hi CD62Llo effector CD8 T cells and B220+ B cells in CD11c+ cell-depleted mice versus controls. CD11c+ depletion attenuated SRA matrix degradation indicated by decreased neutrophil elastase activity (P=0.014), lower elastin degradation score (P=0.012) and higher collagen content (P=0.002)., Conclusion: CD11c+ cell-depletion inhibited experimental AAA development and growth associated with down-regulation of circulating effector T cells and attenuated matrix degradation. The findings suggest involvement of autoreactive immune cells in AAA pathogenesis., (© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

CD4 + CD25 + regulatory T cells (Tregs) have been shown to protect against the development of abdominal aortic aneurysm (AAA). Cyclooxygenase-2 (COX-2), a pro-inflammatory protein, can convert arachidonic acid into prostaglandins (PGs). The present study was aimed to investigate the effect of Tregs on COX-2 expression in angiotension II (Ang II)-induced AAA in ApoE -/- mice. Tregs were injected via tail vein in every 2 weeks. Ang II was continuously infused by a micropump for 28 days to induce AAA. In vivo, compared with the control group, adoptive transfer of Tregs significantly reduced the incidence of AAA, maximal diameter, and the mRNA and protein expression of COX-2 in mice. Immunofluorescence showed that Tregs treatment reduced COX-2 expression both in smooth muscle cells (SMCs) and macrophages in AAA. In vitro, the Western blot analysis showed that Tregs reduced Ang II-induced COX-2 expression in macrophages and SMCs. Meanwhile, ELISA showed that Tregs reduced Ang II-induced prostaglandin E 2 (PGE 2 ) secretion. Moreover, Tregs increased SMC viability and induced transition of macrophages phenotype from M1 to M2. In conclusion, Tregs treatment dramatically decreased the expression of COX-2 in vivo and in vitro, suggesting that Tregs could protect against AAA through inhibition of COX-2. The study may shed light on the immune treatment of AAA., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Abdominal Aortic Aneurysm (AAA) is a major cause of cardiovascular mortality. Adverse changes in vascular phenotype act in concert with chronic inflammation to promote AAA progression. Perivascular adipose tissue (PVAT) helps maintain vascular homeostasis but when inflamed and dysfunctional, can also promote vascular pathology. Previous studies suggested that PVAT may be an important site of vascular inflammation in AAA; however, a detailed assessment of leukocyte populations in human AAA, their anatomic location in the vessel wall and correlation to AAA size remain undefined. Accordingly, we performed in depth immunophenotyping of cells infiltrating the pathologically altered perivascular tissue (PVT) and vessel wall in AAA samples at the site of maximal dilatation ( n = 51 patients). Flow cytometry revealed that T cells, rather than macrophages, are the major leukocyte subset in AAA and that their greatest accumulations occur in PVT. Both CD4 + and CD8 + T cell populations are highly activated in both compartments, with CD4 + T cells displaying the highest activation status within the AAA wall. Finally, we observed a positive relationship between T cell infiltration in PVT and AAA wall. Interestingly, only PVT T cell infiltration was strongly related to tertiles of AAA size. In summary, this study highlights an important role for PVT as a reservoir of T lymphocytes and potentially as a key site in modulating the underlying inflammation in AAA.

The objectives of this study were to evaluate patients with aortic abdominal aneurysm (AAA) with regard to immunoglobulin (Ig)G4-related disease (IgG4-RD). IgG4-RD represents a recently defined condition comprised of a collection of disorders characterized by IgG4 hypergammaglobulinemia, the presence of IgG4-positive plasma cells in organs affected with fibrotic or sclerotizing changes and typical histopathological features. It was identified as a possible cause of vasculitis in large vessels. Studies have been published on a possible association between inflammatory aortic or cardiovascular disease and IgG4-RD. We examined 114 patients with AAA requiring surgery in order to identify findings which are characteristic of IgG4-RD. Aneurysm samples from seven patients showed histopathological features consistent with IgG4-RD and the presence of IgG4 + plasma cells. Only two of these seven patients showed elevated IgG4 serum levels higher 1·35 g/l. In five of the patients, the concentration of serum IgG4 was lower than 1·20 g/l, with the number of IgG4 + plasma cells being higher than 50/high-power field. These findings were consistent with AAA being a heterogeneous group of inflammatory diseases with different pathogenesis., (© 2019 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology.)

Objective: Macrophages play a critical role in the initiation and progression of abdominal aortic aneurysm (AAA) and are classically distinguished into M1 "proinflammatory" and M2 "anti-inflammatory" macrophages. Topical application of elastase associated with transforming growth factor β (TGF-β) systemic neutralization reproduces the main pathologic features of human AAA, offering a new model to investigate their role. The aim of this study was to investigate whether macrophages contribute to the expression of canonical M1/M2 markers in the aorta in the AAA model induced by elastase and systemic blockade of TGF-β and whether blocking of TGF-β activity affects macrophage phenotype and the expression of the M2 marker arginase 1 (ARG1)., Methods: C57Bl/6J male mice (6-8 weeks old) were randomly assigned to three experimental groups: mice that had local application of heat-inactivated elastase or elastase and mice that had elastase application and received injection of anti-TGF-β (elastase + anti-TGF-β group). Monocyte-macrophage depletion was achieved in the elastase + anti-TGF-β group using liposome clodronate. Macrophage phenotype was characterized by quantitative polymerase chain reaction, flow cytometry, and immunohistochemistry. Human infrarenal AAA tissues (n = 10) were obtained to analyze ARG1 expression., Results: Analysis of gene expression in the infrarenal aortic wall revealed that after 14 days, no significant difference for the expression of CCL2, NOS2, and Ym1/2 was observed in the elastase group compared with the elastase + anti-TGF-β group, whereas the expression of ARG1, interleukin (IL) 1β, and IL-6 was significantly increased. Macrophage depletion in the elastase + anti-TGF-β group led to a significant decrease of IL-1β, IL-6, ARG1, and Ym1/2 gene expression. Immunofluorescent staining confirmed that TGF-β neutralization significantly enhanced ARG1 protein expression in the aneurysmal tissue. Flow cytometry analysis revealed an increase of macrophages expressing ARG1 in the aorta of mice treated with elastase + anti-TGF-β compared with the elastase group, and their proportion increased with aneurysmal dilation. In humans, ARG1 protein expression was increased in aneurysmal tissues compared with controls, and positive cells were mainly found in the adventitia., Conclusions: TGF-β neutralization finely tunes macrophage phenotype in elastase-induced AAA and leads to an increase in ARG1 gene and protein expression in the aortic wall. Even if further studies are required to elucidate its role in AAA development, ARG1 could represent a new prognostic or therapeutic target in aneurysmal disease., (Copyright © 2018 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Abdominal aortic aneurysm (AAA) is a life-threatening immunological disease responsible for 1 to 2% of all deaths in 65 year old or older individuals. Although mononuclear cell infiltrates have been demonstrated in AAA lesions and autoimmunity may be responsible for the initiation and account for the propagation of the disease, the information available about the pathogenesis of AAA is limited. To examine whether AAA lesions from patients with AAA contain clonally expanded α-chain TCR transcripts, we amplified by the non-palindromic adaptor-PCR (NPA-PCR)/Vα-specific PCR and/or the Vα-specific PCR these α-chain TCR transcripts. The amplified transcripts were cloned and sequenced. Substantial proportions of identical α-chain TCR transcripts were identified in AAA lesions of 4 of 5 patients, demonstrating that clonally expanded T cells are present in these AAA lesions. These results were statistically significant by the bimodal distribution. Three of 5 of these patients were typed by DNA-based HLA-typing and all three expressed DRB1 alleles containing the DRβGln70 amino acid residue that has been demonstrated to be associated with AAA. All three patients exhibited clonally expanded T cells in AAA lesions. Four of the 5 patients with AAA who exhibited clonal expansions of α-chain TCR transcripts, also exhibited clonal expansions of β-chain TCR transcripts in AAA lesions, as we have demonstrated previously (J Immunol 192:4897, 2014). αβ TCR-expressing T cells infiltrating AAA lesions contain T-cell clones which have undergone proliferation and clonal expansion in vivo in response to as yet unidentified specific antigens that may be self or nonself. These results provide additional evidence supporting the hypothesis that AAA is a specific antigen-driven T-cell autoimmune disease., Competing Interests: The authors have declared that no competing interests exist.

There is some evidence that periodontitis increases the risk of atherothrombosis. Abdominal aortic aneurysm (AAA) is a cardiovascular disease with specific risk factors and physiopathological mechanisms that can lead to rupture in the absence of treatment. The aim of the present systematic review was to explore the influence of periodontitis on the progression of AAAs as a specific disease. A systematic search in PubMed/MEDLINE and Embase databases was performed. Human and animal studies exploring the influence of periodontal pathogens on the progression of AAA were considered for inclusion. After systematic screening, 5 articles were included in the review. Due to the heterogeneity of the selected studies, a meta-analysis could not be performed. The descriptive analyses of the studies emphasized that periodontal pathogens or their by-products contribute to systemic and local innate immunity likely to be associated with AAA physiopathology. Periodontitis seems to play a role in the development and progression of AAA. The present systematic review suggests that the presence of periodontal bacteria in the bloodstream or in situ in the vascular lesion is a risk associated with aneurysmal disease progression.

Abdominal aortic aneurysm (AAA) is a serious condition of unclear pathogenesis and progression. Two samples were collected from 48 patients during AAA surgery. One sample was collected from the aneurysm, the other from the aneurysm proximal neck where the tissue did not exhibit any aneurysmal changes. Subsequently, gene expression profiles using microarrays (Illumina) were compared in RNA extracted from the samples. Overall, 2,185 genes were found to be upregulated and 2,100 downregulated; from which 158 genes had a different expression with FDR<0.05 (False Discovery Rate) and FC>/=2 (Fold Change). Of this number, 115 genes were over-expressed and 43 under-expressed. The analysis of the gene list based on their biological pathways revealed that the regulation of inflammation was mediated by chemokine and cytokine signaling pathways, the integrin signaling pathway, and T and B cell activation. Moreover, a change was identified in the expression of genes involved in both intercellular and intracellular signaling systems.

Vascular inflammation via T-cell-mediated immune responses has been shown to be critically involved in the pathogenesis of abdominal aortic aneurysm (AAA). T-cell coinhibitory molecule cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is known to act as a potent negative regulator of immune responses. However, the role of this molecule in the development of AAA remains completely unknown. We determined the effects of CTLA-4 overexpression on experimental AAA. We continuously infused CTLA-4 transgenic (CTLA-4-Tg)/apolipoprotein E-deficient (Apoe -/- ) mice or control Apoe -/- mice fed a high-cholesterol diet with angiotensin II by implanting osmotic mini-pumps and evaluated the development of AAA. Ninety percent of angiotensin II-infused mice developed AAA, with 50% mortality because of aneurysm rupture. Overexpression of CTLA-4 significantly reduced the incidence (66%), mortality (26%), and diameter of AAA. These protective effects were associated with a decreased number of effector CD4 + T cells and the downregulated expression of costimulatory molecules CD80 and CD86, ligands for CTLA-4, on CD11c + dendritic cells in lymphoid tissues. CTLA-4-Tg/Apoe -/- mice had reduced accumulation of macrophages and CD4 + T cells, leading to attenuated aortic inflammation, preserved vessel integrity, and decreased susceptibility to AAA and aortic rupture. Our findings suggest T-cell coinhibitory molecule CTLA-4 as a novel therapeutic target for AAA.