Deciphering the causal association and underlying transcriptional mechanisms between telomere length and abdominal aortic aneurysm.

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.

Circulating monocyte populations as biomarker for abdominal aortic aneurysms: a single-center retrospective cohort study.

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.

Unleashing PD-1: a duel of immunity in aortic aneurysm formation.

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.

Single-Cell RNA Sequencing Deconstructs the Distribution of Immune Cells Within Abdominal Aortic Aneurysms in Mice.

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.

Artificial intelligence-driven multiomics predictive model for abdominal aortic aneurysm subtypes to identify heterogeneous immune cell infiltration and predict disease progression.

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-1ß, and IL-8 were upregulated in AAA. CXCL1 silencing downregulated NF-κB, interleukin-1ß, 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.

Assessing the causal relationship between circulating immune cells and abdominal aortic aneurysm by bi-directional Mendelian randomization analysis.

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.

Causal relationship between immune cells and aortic aneurysms: a Mendelian randomization study.

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.

Deciphering Abdominal Aortic Diseases Through T-Cell Clonal Repertoire of Perivascular Adipose Tissue.

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 ß-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 ß-chain clonotypes that distinguished AAA and aortic occlusive disease with very high accuracy. We also found that the T-cell receptor ß-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.

Unravelling CD4+ T cell diversity and tissue adaptation of Tregs in abdominal aortic aneurysms through single-cell sequencing.

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.

Group 2 Innate Lymphoid Cells Protect Mice from Abdominal Aortic Aneurysm Formation via IL5 and Eosinophils.

Development of abdominal aortic aneurysms (AAA) enhances lesion group-2 innate lymphoid cell (ILC2) accumulation and blood IL5. ILC2 deficiency in Rorafl/fl Il7rCre/+ mice or induced ILC2 depletion in Icosfl-DTR-fl/+ Cd4Cre/+ 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 Rorafl/fl Il7rCre/+ 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 Ly6Chi monocyte polarization. Reconstitution of WT EOS and ILC2 but not Il5-/- ILC2 slows AAA growth in Rorafl/fl Il7rCre/+ mice by increasing systemic EOS. Besides regulating SMC pathobiology, ILC2 play an indirect role in AAA protection via the IL5 and EOS mechanism.

Induction of CD73 prevents death after emergency open aortic surgery for a ruptured abdominal aortic aneurysm: a randomized, double-blind, placebo-controlled study.

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).

Differences in local immune cell landscape between Q fever and atherosclerotic abdominal aortic aneurysms identified by multiplex immunohistochemistry.

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].

Dapagliflozin Ameliorates the Formation and Progression of Experimental Abdominal Aortic Aneurysms by Reducing Aortic Inflammation in Mice.

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.

Hexarelin attenuates abdominal aortic aneurysm formation by inhibiting SMC phenotype switch and inflammasome activation.

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.

Temporal and Quantitative Analysis of Aortic Immunopathologies in Elastase-Induced Mouse Abdominal Aortic Aneurysms.

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.

Tryptophan Catabolism and Inflammation: A Novel Therapeutic Target For Aortic Diseases.

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.

Reversal of elastase-induced abdominal aortic aneurysm following the delivery of nanoparticle-based pentagalloyl glucose (PGG) is associated with reduced inflammatory and immune markers.

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.

B Cell-Activating Factor Antagonism Attenuates the Growth of Experimental Abdominal Aortic Aneurysm.

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.

Surgical strategy of IgG4-related inflammatory abdominal aortic aneurysm with preoperative steroid therapy: A case report.

Immunoglobulin G4 (IgG4)-related disease, characterized by high serum IgG4 concentrations and IgG4-positive plasma cell infiltration, often presents as an inflammatory aneurysm. We herein report the case of a 78 year-old man, presenting with elevated inflammatory markers and IgG4 concentrations, who was diagnosed with IgG4-related inflammatory abdominal aortic aneurysm with dense perianeurysmal fibrosis. Before the surgical intervention, steroid therapy was administered to resolve his perianeurysmal inflammatory fibrosis. Half a year after the initiation of steroid therapy, there was an improvement in serum inflammatory markers and IgG4 concentrations, and the perianeurysmal fibrosis had regressed. Thus, we performed a surgical intervention including resection of the aneurysm and interposition with a prosthetic graft. Histopathological examination demonstrated few IgG4-positive plasma cells were distributed in the adventitia, which was suspected to be associated with the preoperative steroid therapy. This case study suggests preoperative steroid therapy is a useful therapeutic strategy for IgG4-related abdominal aortic aneurysm because it allows the use of open surgical procedures with reduced surgical risk.

Paeonol Ameliorates Abdominal Aortic Aneurysm Progression by the NF-κB Pathway.

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.