Human Abdominal Aortic Aneurysm Research Articles

Itaconate Prevents Abdominal Aortic Aneurysm Formation Through Inhibiting Inflammation Via Activation of Nrf2

Background: Identifying effective drugs to suppress vascular inflammation is a promising strategy to delay the progression of abdominal aortic aneurysm (AAA). Itaconate has a vital role in regulating inflammatory activation in various inflammatory diseases. However, the role of itaconate in the progression of AAA is unknown. In this study, we explored the inhibitory effect of itaconate on AAA formation and its underlying mechanisms. Methods: Quantitative PCR, western blotting and immunohistochemistry were used to determine Irg1 and downstream Nrf2 expression in human and mouse AAA samples. Liquid chromatograph-mass spectrometry (LC-MS) analysis was performed to measure the abundance of itaconate. OI treatment and Irg1 knockdown were performed to study the role of OI in AAA formation. Nrf2 intervention in vivo were performed to detect the critical role of Nrf2 in the beneficial effect of OI on AAA. Findings: We found that itaconate suppressed the formation of angiotensin II (Ang II)-induced AAA in apolipoprotein E-deficient (Apoe-/-) mice, while Irg1 deficiency exerted the opposite effects. Mechanistically, itaconate inhibited vascular inflammation by enabling Nrf2 to function as a transcriptional repressor of downstream inflammatory genes via alkylation of Keap1. Moreover, Nrf2 deficiency significantly aggravated inflammatory factor expression and promoted AAA formation. In addition, Keap1 overexpression significantly promoted Ang II-induced AAA formation, which were inhibited by itaconate. Interpretation: Itaconate inhibited AAA formation by suppressing vascular inflammation, and therapeutic approaches to increase itaconate are potentially beneficial for preventing AAA formation. Funding: National Natural Science Foundations of China and Guangzhou regenerative medicine and Health Laboratory of Guangdong. Declaration of Interest: None. Ethical Approval: Human AAA samples were obtained from patients undergoing open surgical repair according to protocols approved by the Research Ethics Committees of Nanfang Hospital (ethical approval number: NFEC-2019-086). All animal protocols were approved by the Institutional Animal Care and Use Committee at Southern Medical University.

Depletion of CD11c+ dendritic cells in apolipoprotein E-deficient mice limits angiotensin II-induced abdominal aortic aneurysm formation and growth.

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. 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. 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). 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.

Let-7f: A New Potential Circulating Biomarker Identified by miRNA Profiling of Cells Isolated from Human Abdominal Aortic Aneurysm.

Abdominal aortic aneurysm (AAA) is a progressive vascular disease responsible for 1–4% of the deaths in elderly men. This study aimed to characterize specific microRNA (miRNA) expression in aneurysmal smooth muscle cells (SMCs) and macrophages in order to identify circulating miRNAs associated with AAA. We screened 850 miRNAs in aneurysmal SMCs, M1 and M2 macrophages, and in control SMCs isolated by micro-dissection from aortic biopsies using microarray analysis. In all, 92 miRNAs were detected and 10 miRNAs were selected for validation by qRT-PCR in isolated cells (n = 5), whole control and aneurysmal aorta biopsies (n = 13), and plasma from patients (n = 24) undergoing AAA (over 50 mm) repair matched to patients (n = 18) with peripheral arterial disease (PAD) with atherosclerosis but not AAA. Seven miRNAs were modulated similarly in all aneurysmal cells. The Let-7f was downregulated in aneurysmal cells compared to control SMCs with a significant lower expression in M1 compared to M2 macrophages (0.1 fold, p = 0.03), correlated with a significant downregulation in whole aneurysmal aorta compared to control aorta (0.2 fold, p = 0.03). Significant levels of circulating let-7f (p = 0.048) were found in AAA patients compared to PAD patients with no significant correlation with aortic diameter (R2 = 0.03). Our study underlines the utility of profiling isolated aneurysmal cells to identify other miRNAs for which the modulation of expression might be masked when the whole aorta is used. The results highlight let-7f as a new potential biomarker for AAA.

AAA 25. Cell-Specific Profiling of Transcriptional Landscape in Human Abdominal Aortic Aneurysm by Single-Cell RNA Sequencing

AAA 25. Cell-Specific Profiling of Transcriptional Landscape in Human Abdominal Aortic Aneurysm by Single-Cell RNA Sequencing

ULTRASOUND-TARGETED MIRNA-26A THERAPY FOR ABDOMINAL AORTIC ANEURYSM

Abdominal aortic aneurysm (AAA) affects ∼5% of older adults. AAA is characterized by marked vessel inflammation, human aortic smooth muscle cell (haSMC) depletion and extracellular matrix (ECM) degradation. MicroRNA-26a (miR-26a) is reduced in human AAA and murine models and may contribute to haSMC apoptosis. We hypothesize that targeted miR-26a therapy via ultrasound-targeted microbubble destruction (UTMD) will reverse the AAA inflammatory response, replenish haSMC content and prevent AAA progression.

Dysregulation of microRNAs and target genes networks in human abdominal aortic aneurysm tissues.

BackgroundAbdominal aortic aneurysm (AAA) is a pathological enlargement of infrarenal aorta close to the aortic bifurcation, and it is an important cause of mortality in the elderly. Therefore, the biomarker identification for early diagnosis is of great interest for clinical benefit. It is known that microRNAs (miRNAs) have important roles via target genes regulation in many diseases. This study aimed to identify miRNAs and their target genes involved in the pathogenesis of AAA.MethodsTissue samples were obtained from patients who underwent AAA surgery and from organ donors (control group). Quantitative PCR Array was applied to assess 84 genes and 384 miRNAs aiming to identify differentially expressed targets (AAA n = 6, control n = 6), followed by validation in a new cohort (AAA n = 18, control n = 6) by regular qPCR. The functional interaction between validated miRNAs and target genes was performed by the Ingenuity Pathway Analysis (IPA) software.ResultsThe screening cohort assessed by PCR array identified 10 genes and 59 miRNAs differentially expressed (≥2-fold change, p<0.05). Among these, IPA identified 5 genes and 9 miRNAs with paired interaction. ALOX5, PTGIS, CX3CL1 genes, and miR-193a-3p, 125b-5p, 150-5p maintained a statistical significance in the validation cohort. IPA analysis based on the validated genes and miRNAs revealed that eicosanoid and metalloproteinase/TIMP synthesis are potentially involved in AAA.ConclusionPaired interactions of differentially expressed ALOX5, PTGIS, CX3CL1 genes, and miR-193b-3p, 125b-5p, 150-5p revealed a potentially significant role of the eicosanoid synthesis and metalloproteinase/TIMP pathways in the AAA pathogenesis.

The Relationship Between Macrophages, Matrix Metalloproteinase-12, Interleukin-6, and Intraluminal Thrombus in Human Abdominal Aortic Aneurysms

The Relationship Between Macrophages, Matrix Metalloproteinase-12, Interleukin-6, and Intraluminal Thrombus in Human Abdominal Aortic Aneurysms

Pharmacological inhibition of Notch signaling regresses pre-established abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is characterized by transmural infiltration of myeloid cells at the vascular injury site. Previously, we reported preventive effects of Notch deficiency on the development of AAA by reduction of infiltrating myeloid cells. In this study, we examined if Notch inhibition attenuates the progression of pre-established AAA and potential implications. Pharmacological Notch inhibitor (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-(S)-phenylglycine t-butyl ester; DAPT) was administered subcutaneously three times a week starting at day 28 of angiotensin II (AngII) infusion. Progressive increase in pulse wave velocity (PWV), maximal intra-luminal diameter (MILD) and maximal external aortic diameter (MEAD) were observed at day 56 of the AngII. DAPT prevented such increase in MILD, PWV and MEAD (P < 0.01). Histologically, the aortae of DAPT-treated Apoe−/− mice had significant reduction in inflammatory response and elastin fragmentation. Naked collagen microfibrils and weaker banded structure observed in the aortae of Apoe−/− mice in response to AngII, were substantially diminished by DAPT. A significant decrease in the proteolytic activity in the aneurysmal tissues and vascular smooth muscle cells (vSMCs) was observed with DAPT (P < 0.01). In human and mouse AAA tissues, increased immunoreactivity of activated Notch signaling correlated strongly with CD38 expression (R2 = 0.61). Collectively, we propose inhibition of Notch signaling as a potential therapeutic target for AAA progression.

T Cells Are Dominant Population in Human Abdominal Aortic Aneurysms and Their Infiltration in the Perivascular Tissue Correlates With Disease Severity.

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.

AEBP1 Promotes the Occurrence and Development of Abdominal Aortic Aneurysm by Modulating Inflammation via the NF-κB Pathway.

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.

Myeloid related protein 8/14 is a new candidate biomarker and therapeutic target for abdominal aortic aneurysm

Open surgical or percutaneous endovascular (EVAR) intervention is the only approved treatment for abdominal aortic aneurysm (AAA). Novel targeted therapy and companion diagnostic are needed. Our study aimed to investigate the expression of myeloid related protein 8/14 (MRP8/14) in AAA and explore whether MRP8/14 can be a biomarker and therapeutic target for AAA. The serum levels of MRP8/14 and inflammatory factors including TNF-α, IL-1β, and IL-6 were increased in 20 human AAA patients compared to healthy people by ELISA assay. The mRNA and protein expressions of MRPs in AAA tissues of AAA patient were significantly elevated when compared with the levels in adjacent non-aneurysmal aortic segments in AAA patients. through PCR and western blot analysis. Correlation analysis and receiver operating characteristic (ROC) curve analysis confirmed that MRP8/14 was secreted into the serum and possessed the potential diagnostic value. Rat AAA models established by perfusion porcine pancreatic elastase and murine macrophage RAW264.7 cells were used to evaluate the mechanisms of MRP8/14 after treatment with antibodies. Similarly, MRP8, MRP14, and MRP8/14 were highly expressed in rat AAA model, while the administrations of antibodies of MRPs significantly reversed the improvement expressions of MRP8 and MRP14. In RAW264.7 cells, MRPs especially for MRP8/14 obviously increased the levels of MMP-2 and MMP-9. Under MRP8/14 stimulation, the antibodies of MRPs recovered the expressions of MMP-2 and MMP-9. Anti MRP8/14 antibody exhibited the strongest effect in the experiments. Our results indicated that MRP8/14 was associated with AAA presence and progression and could be considered as a biomarker for AAA diagnose. Anti MRP8/14 can be a potential therapeutic target for treatment of AAA.

Interleukin-12 and -23 blockade mitigates elastase-induced abdominal aortic aneurysm

Macrophages play an important role in the inflammatory process that contributes to the development of abdominal aortic aneurysm (AAA). Studies of human and mouse AAA tissue reveal expanded populations of macrophages producing an abundance of pro-inflammatory cytokines, including TNF-α, IL-12p40 and high level of metalloprotease 9 (MMP-9) at the late stages of disease. Herein, we show that blockade of IL-12p40 in the early phase of aneurysm development suppresses macrophage expansion, inflammatory cytokine and MMP-9 production and mitigates AAA development. Since IL-12 and IL-23 are related cytokines that share the common p40 subunit, we also evaluate the effect of direct IL-23 blockade on the development of AAA. Specific IL-23p19 blockade prevents AAA progression with the same efficiency as IL-12p40 antagonism, suggesting that the efficacy of anti-IL-12p40 treatment may reflect IL-23 blockade. IL-12p40 and IL-23p19 are also abundantly expressed in human AAA tissue. Our findings have potential translational value since IL-12p40 and IL-23p19 antagonists already exist as FDA-approved therapeutics for various chronic inflammatory conditions.

Tropoelastin: an in vivo imaging marker of dysfunctional matrix turnover during abdominal aortic dilation.

AimsDysfunctional matrix turnover is present at sites of abdominal aortic aneurysm (AAA) and leads to the accumulation of monomeric tropoelastin rather than cross-linked elastin. We used a gadolinium-based tropoelastin-specific magnetic resonance contrast agent (Gd-TESMA) to test whether quantifying regional tropoelastin turnover correlates with aortic expansion in a murine model. The binding of Gd-TESMA to excised human AAA was also assessed.Methods and resultsWe utilized the angiotensin II (Ang II)-infused apolipoprotein E gene knockout (ApoE-/-) murine model of aortic dilation and performed in vivo imaging of tropoelastin by administering Gd-TESMA followed by late gadolinium enhancement (LGE) magnetic resonance imaging (MRI) and T1 mapping at 3 T, with subsequent ex vivo validation. In a cross-sectional study (n = 66; control = 11, infused = 55) we found that Gd-TESMA enhanced MRI was elevated and confined to dilated aortic segments (control: LGE=0.13 ± 0.04 mm2, control R1= 1.1 ± 0.05 s-1 vs. dilated LGE=1.0 ± 0.4 mm2, dilated R1 =2.4 ± 0.9 s-1) and was greater in segments with medium (8.0 ± 3.8 mm3) and large (10.4 ± 4.1 mm3) compared to small (3.6 ± 2.1 mm3) vessel volume. Furthermore, a proof-of-principle longitudinal study (n = 19) using Gd-TESMA enhanced MRI demonstrated a greater proportion of tropoelastin: elastin expression in dilating compared to non-dilating aortas, which correlated with the rate of aortic expansion. Treatment with pravastatin and aspirin (n = 10) did not reduce tropoelastin turnover (0.87 ± 0.3 mm2 vs. 1.0 ± 0.44 mm2) or aortic dilation (4.86 ± 2.44 mm3 vs. 4.0 ± 3.6 mm3). Importantly, Gd-TESMA-enhanced MRI identified accumulation of tropoelastin in excised human aneurysmal tissue (n = 4), which was confirmed histologically.ConclusionTropoelastin MRI identifies dysfunctional matrix remodelling that is specifically expressed in regions of aortic aneurysm or dissection and correlates with the development and rate of aortic expansion. Thus, it may provide an additive imaging marker to the serial assessment of luminal diameter for surveillance of patients at risk of or with established aortopathy.

Integrated Physiological and Biochemical Assessments for the Prediction of Growth of Abdominal Aortic Aneurysms in Humans.

Integrated Physiological and Biochemical Assessments for the Prediction of Growth of Abdominal Aortic Aneurysms in Humans.

Apelin protects against abdominal aortic aneurysm and the therapeutic role of neutral endopeptidase resistant apelin analogs.

Abdominal aortic aneurysm (AAA) remains the second most frequent vascular disease with high mortality but has no approved medical therapy. We investigated the direct role of apelin (APLN) in AAA and identified a unique approach to enhance APLN action as a therapeutic intervention for this disease. Loss of APLN potentiated angiotensin II (Ang II)-induced AAA formation, aortic rupture, and reduced survival. Formation of AAA was driven by increased smooth muscle cell (SMC) apoptosis and oxidative stress in Apln-/y aorta and in APLN-deficient cultured murine and human aortic SMCs. Ang II-induced myogenic response and hypertension were greater in Apln-/y mice, however, an equivalent hypertension induced by phenylephrine, an α-adrenergic agonist, did not cause AAA or rupture in Apln-/y mice. We further identified Ang converting enzyme 2 (ACE2), the major negative regulator of the renin-Ang system (RAS), as an important target of APLN action in the vasculature. Using a combination of genetic, pharmacological, and modeling approaches, we identified neutral endopeptidase (NEP) that is up-regulated in human AAA tissue as a major enzyme that metabolizes and inactivates APLN-17 peptide. We designed and synthesized a potent APLN-17 analog, APLN-NMeLeu9-A2, that is resistant to NEP cleavage. This stable APLN analog ameliorated Ang II-mediated adverse aortic remodeling and AAA formation in an established model of AAA, high-fat diet (HFD) in Ldlr-/- mice. Our findings define a critical role of APLN in AAA formation through induction of ACE2 and protection of vascular SMCs, whereas stable APLN analogs provide an effective therapy for vascular diseases.

ASB17061, a novel chymase inhibitor, prevented the development of angiotensin II-induced abdominal aortic aneurysm in apolipoprotein E-deficient mice

Our aim was to examine the effects of ASB17061, an orally active novel chymase inhibitor, on angiotensin II–induced abdominal aortic aneurysm (AAA) in apolipoprotein E–deficient mice. Oral administration of ASB17061 (10 mg/kg) significantly suppressed angiotensin II–induced AAA formation in these mice. The pro-matrix metalloproteinase-9 (pro-MMP-9) level in AAA lesions was significantly suppressed by ASB17061 treatment, indicating that ASB17061 inhibited the accumulation of pro-MMP-9–producing cells in AAA lesions. Mouse mast cell protease 4 (mMCP-4, human chymase ortholog) was injected into BALB/c mice intraperitoneally to examine the ability of mMCP-4 to induce the accumulation of pro-MMP-9–producing cells. An intraperitoneal injection of mMCP-4 induced the accumulation of pro-MMP-9–producing cells including CD11b + Gr-1 + cells. Taken together, these data indicate that ASB17061 is a promising novel oral therapeutic agent for human AAA.

Impaired smooth muscle cell contractility as a novel concept of abdominal aortic aneurysm pathophysiology

Ruptured abdominal aortic aneurysms (AAA) are associated with overall mortality rates up to 90%. Despite extensive research, mechanisms leading to AAA formation and advancement are still poorly understood. Smooth muscle cells (SMC) are predominant in the aortic medial layer and maintain the wall structure. Apoptosis of SMC is a well-known phenomenon in the pathophysiology of AAA. However, remaining SMC function is less extensively studied. The aim of this study is to assess the in vitro contractility of human AAA and non-pathologic aortic SMC. Biopsies were perioperatively harvested from AAA patients (n = 21) and controls (n = 6) and clinical data were collected. Contractility was measured using Electric Cell-substrate Impedance Sensing (ECIS) upon ionomycin stimulation. Additionally, SMC of 23% (5 out of 21) of AAA patients showed impaired maximum contraction compared to controls. Also, SMC from patients who underwent open repair after earlier endovascular repair and SMC from current smokers showed decreased maximum contraction vs. controls (p = 0.050 and p = 0.030, respectively). Our application of ECIS can be used to study contractility in other vascular diseases. Finally, our study provides with first proof that impaired SMC contractility might play a role in AAA pathophysiology.

High-density Lipoproteins (HDLs): Biomarkers or bio-actors of abdominal aortic aneurysmal disease?

High-density Lipoproteins (HDLs): Biomarkers or bio-actors of abdominal aortic aneurysmal disease?

LncRNA H19 promotes vascular inflammation and abdominal aortic aneurysm formation by functioning as a competing endogenous RNA

Abdominal aortic aneurysm (AAA) is accepted as a chronic vascular inflammatory disease. However, how the inflammatory response is regulated during AAA formation is not fully understood. This study was undertaken to determine whether the long noncoding RNA (lncRNA) H19 (H19) promotes AAA formation by enhancing aortic inflammation. qRT-PCR detected the upregulation of H19 in human and mouse AAA tissue samples. Co-staining for H19 and the macrophage marker MAC-2 showed that H19 was located in vascular smooth muscle cells (VSMCs) and infiltrating aortic macrophages. In vivo overexpression of H19 increased vascular inflammation and induced AAA formation, which was supported by exacerbated aortic morphology, maximum aortic diameter values, elastin degradation, expression of interleukin-6 (IL-6) and macrophage chemoattractant protein-1 (MCP-1), and macrophage infiltration. H19 suppression resulted in the opposite effects. A rescue experiment indicated that IL-6 neutralization significantly mitigated the aortic inflammation and AAA formation evoked by H19 overexpression. Luciferase reporter assays and ex vivo experiments using VSMCs and macrophages confirmed that H19 induced aneurysm formation in part via endogenous competition with the let-7a microRNA to induce the transcription of its target gene, IL-6. This mechanism was further validated by in vivo experiments using a mutant H19 that could not effectively bind let-7a. Collectively, our study revealed a pathogenic H19/let-7a/IL-6 inflammatory pathway in AAA formation, which offers a new potential therapeutic strategy for AAA.

APOA1 oxidation is associated to dysfunctional high-density lipoproteins in human abdominal aortic aneurysm

BackgroundHigh-density lipoproteins (HDL) are a complex mixture of lipids and proteins with vasculoprotective properties. However, HDL components could suffer post-translational modifications (PTMs) under pathological conditions, leading to dysfunctional HDL. We studied whether HDL are modified in abdominal aortic aneurysm (AAA) and the effect on HDL functionality.MethodsHDL were isolated by ultracentrifugation from AAA tissue (HDL-T) and from plasma of healthy volunteers and then incubated with AAA tissue-conditioned medium (HDL-AAA CM). PTMs from these particles were characterized using Comet-PTM. The ability of HDL-AAA CM for promoting cholesterol efflux was determined ex vivo and in vivo by using J774A.1 [3H]cholesterol-labeled mouse macrophages and after injecting [3H]cholesterol-labeled mouse macrophages and HDL into the peritoneal cavity of wild-type C57BL/6 mice, respectively. Trp50 and Trp108 oxidized forms of APOA1 in HDL incubated with conditioned-medium of activated neutrophils and in plasma of AAA patients and controls were measured by targeted parallel reaction monitoring.FindingsOxidation was the most prevalent PTM in apolipoproteins, particularly in APOA1. Trp50 and Trp108 in APOA1 were the residues most clearly affected by oxidation in HDL-T and in HDL-AAA CM, when compared to their controls. In addition, cholesterol efflux was decreased in macrophages incubated with HDL-AAA CM in vitro and a decreased macrophage-to-serum reverse cholesterol transport was also observed in mice injected with HDL-AAA CM. Finally, both oxidized Trp50 and Trp108 forms of APOA1 were increased in HDL incubated with conditioned-medium of activated neutrophils and in plasma of AAA patients in relation to controls.InterpretationOxidative modifications of HDL present in AAA tissue and plasma were closely associated with the loss of vasculoprotective properties of HDL in AAA.FundMINECO, ISCiii-FEDER, CIBERDEM, CIBERCV and LA CAIXA.