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1.
Eur Rev Med Pharmacol Sci ; 26(8): 2847-2860, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35503629

RESUMO

OBJECTIVE: An abdominal aortic aneurysm (AAA) is a potentially fatal disease associated with a high risk of rupture. AAA is pathologically distinguished by atherosclerotic thrombosis, immune cell infiltration, smooth muscle cell apoptosis, and extracellular matrix degradation. Given that there are no effective target treatments, once ruptured, AAA leads to high mortality with few long-term survivors. The goal of this study is to identify novel key pathways and hub genes involved in AAA formation with the aim of providing promising therapeutic targets for AAA. MATERIALS AND METHODS: The transcriptome sequencing matrix of GSE47472 and GSE57691 were obtained from the GEO database. These datasets were further merged for differential expression analysis, weighted gene co-expression network analysis (WGCNA), and functional enrichment analysis in R (v4.0.2). A co-expression network was constructed with Cytoscape (v3.8.0) to generate the top 30 hub genes. Hub Genes with high clinical traits and potential values were further verified using a receiver operating characteristic (ROC) curve and qPCR analysis. RESULTS: A total of 745 differentially expressed genes were screened and 14 gene co-expression modules were established. Among these 14 modules, pink modules with a total of 118 genes showed the strongest correlation with AAA pathogenesis. Subsequently, 78 genes associated with a highly relevant clinical trait and the top 30 hub genes were intersected to generate 22 genes. Gene ontology functional enrichment analysis of the 22 genes revealed abnormal expression of genes relating to cell-matrix adhesion and integrin-mediated signaling pathway. LAMA5, ITGA8, ITGA1, and FERMT2 were associated with the integrin-mediated signaling pathway and cell-matrix adhesion while ACTN1 and CX3CL1 were simply associated with the latter. Low expressions of LAMA5, ACTN1, ITGA8, ITGA1, and FERMT2 were further verified through qPCR in a mouse model of AAA. CONCLUSIONS: Low expression of partial genes in the integrin signaling pathway was implicated in the function loss of mediated cell-matrix adhesion, which may offer novel targets for therapeutic intervention against AAA.


Assuntos
Aneurisma da Aorta Abdominal , Perfilação da Expressão Gênica/métodos , Integrinas/metabolismo , Transdução de Sinais , Animais , Aneurisma da Aorta Abdominal/patologia , Biologia Computacional , Redes Reguladoras de Genes , Camundongos , Transcriptoma
2.
Sci Rep ; 12(1): 5664, 2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-35383201

RESUMO

Genetic variants that regulate lipid phosphate phosphatase 3 (LPP3) expression are risk factors for the development of atherosclerotic cardiovascular disease. LPP3 is dynamically upregulated in the context of vascular inflammation with particularly heightened expression in smooth muscle cells (SMC), however, the impact of LPP3 on vascular pathology is not fully understood. We investigated the role of LPP3 and lysophospholipid signaling in a well-defined model of pathologic aortic injury and observed Angiotensin II (Ang II) increases expression of PLPP3 in SMCs through nuclear factor kappa B (NF-κB) signaling Plpp3 global reduction (Plpp3+/-) or SMC-specific deletion (SM22-Δ) protects hyperlipidemic mice from AngII-mediated aneurysm formation. LPP3 expression regulates SMC differentiation state and lowering LPP3 levels promotes a fibroblast-like phenotype. Decreased inactivation of bioactive lysophosphatidic acid (LPA) in settings of LPP3 deficiency may underlie these phenotypes because deletion of LPA receptor 4 in mice promotes early aortic dilation and rupture in response to AngII. LPP3 expression and LPA signaling influence SMC and vessel wall responses that are important for aortic dissection and aneurysm formation. These findings could have important implications for therapeutics targeting LPA metabolism and signaling in ongoing clinical trials.


Assuntos
Angiotensina II , Aneurisma da Aorta Abdominal , Miócitos de Músculo Liso , Fosfatidato Fosfatase , Animais , Aneurisma da Aorta Abdominal/patologia , Camundongos , Camundongos Knockout , Miócitos de Músculo Liso/enzimologia , Fosfatidato Fosfatase/metabolismo
3.
Biomolecules ; 12(4)2022 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-35454098

RESUMO

Abdominal aortic aneurysm (AAA), defined as a focal dilation of the abdominal aorta beyond 50% of its normal diameter, is a common and potentially life-threatening vascular disease. The molecular and cellular mechanisms underlying AAA pathogenesis remain unclear. Healthy endothelial cells (ECs) play a critical role in maintaining vascular homeostasis by regulating vascular tone and maintaining an anti-inflammatory, anti-thrombotic local environment. Increasing evidence indicates that endothelial dysfunction is an early pathologic event in AAA formation, contributing to both oxidative stress and inflammation in the degenerating arterial wall. Recent studies utilizing single-cell RNA sequencing revealed heterogeneous EC sub-populations, as determined by their transcriptional profiles, in aortic aneurysm tissue. This review summarizes recent findings, including clinical evidence of endothelial dysfunction in AAA, the impact of biomechanical stress on EC in AAA, the role of endothelial nitric oxide synthase (eNOS) uncoupling in AAA, and EC heterogeneity in AAA. These studies help to improve our understanding of AAA pathogenesis and ultimately may lead to the generation of EC-targeted therapeutics to treat or prevent this deadly disease.


Assuntos
Aneurisma da Aorta Abdominal , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/patologia , Dilatação Patológica , Células Endoteliais/patologia , Humanos , Estresse Oxidativo
4.
Cells ; 11(6)2022 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-35326494

RESUMO

(1) Abdominal aortic aneurysm (AAA) is a silent, progressive disease with significant mortality from rupture. Whilst screening programmes are now able to detect this pathology early in its development, no therapeutic intervention has yet been identified to halt or retard aortic expansion. The inability to obtain aortic tissue from humans at early stages has created a necessity for laboratory models, yet it is essential to create a timeline of events from EARLY to END stage AAA progression. (2) We used a previously validated ex vivo porcine bioreactor model pre-treated with protease enzyme to create "aneurysm" tissue. Mechanical properties, histological changes in the intact vessel wall, and phenotype/function of vascular smooth muscle cells (SMC) cultured from the same vessels were investigated. (3) The principal finding was significant hyperproliferation of SMC from EARLY stage vessels, but without obvious histological or SMC aberrancies. END stage tissue exhibited histological loss of α-smooth muscle actin and elastin; mechanical impairment; and, in SMC, multiple indications of senescence. (4) Aortic SMC may offer a therapeutic target for intervention, although detailed studies incorporating intervening time points between EARLY and END stage are required. Such investigations may reveal mechanisms of SMC dysfunction in AAA development and hence a therapeutic window during which SMC differentiation could be preserved or reinstated.


Assuntos
Aneurisma da Aorta Abdominal , Animais , Aneurisma da Aorta Abdominal/patologia , Diferenciação Celular , Miócitos de Músculo Liso/patologia , Fenótipo , Suínos
5.
Eur J Vasc Endovasc Surg ; 63(4): 632-640, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35277322

RESUMO

OBJECTIVE: The role of atherosclerosis in abdominal aortic aneurysm (AAA) pathogenesis is controversial. The aim of this study was to compare AAA growth in patients who did and did not have concurrent athero-occlusive disease (AOD). METHODS: Patients with an AAA measuring 35 - 49 mm in maximum diameter were recruited as part of the TElmisartan in the management of abdominal aortic aneurysm (TEDY) trial. TEDY participants who had infrarenal aortic volume and orthogonal diameter assessed by computed tomography at entry and at least one other time point during the trial (12 and/or 24 months) were included. AOD was defined by prior diagnoses of coronary heart disease, stroke, or peripheral arterial disease or an ankle brachial pressure index < 0.90. The increase in AAA volume and diameter from entry for participants who did and did not have AOD was assessed using linear mixed effects models; 131 of the 210 participants recruited to TEDY were included. RESULTS: In an unadjusted analysis, the mean (95% confidence interval) annual increases in AAA volume and diameter for participants with AOD were 3.26 (0.82 - 5.70) cm3 and 0.70 (0.19 - 1.22) mm slower than those without AOD, p = .008 and .007 respectively. The association between AOD and significantly slower AAA growth was maintained after adjusting for risk factors and medications, significantly unequally distributed between participants with and without an AOD diagnosis. CONCLUSION: In an exploratory analysis of a selective cohort from the TEDY trial, AOD was associated with slower AAA growth. Validation of these findings in other cohorts is needed.


Assuntos
Aneurisma da Aorta Abdominal , Doença das Coronárias , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/complicações , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/patologia , Humanos , Fatores de Risco , Tomografia Computadorizada por Raios X
6.
Sci Adv ; 8(11): eabm7322, 2022 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-35294231

RESUMO

Pathological vascular remodeling is the underlying cause of atherosclerosis and abdominal aortic aneurysm (AAA). Here, we analyzed the role of galectin-1 (Gal-1), a ß-galactoside-binding protein, as a therapeutic target for atherosclerosis and AAA. Mice lacking Gal-1 (Lgals1-/-) developed severe atherosclerosis induced by pAAV/D377Y-mPCSK9 adenovirus and displayed higher lipid levels and lower expression of contractile markers of vascular smooth muscle cells (VSMCs) in plaques than wild-type mice. Proteomic analysis of Lgals1-/- aortas showed changes in markers of VSMC phenotypic switch and altered composition of mitochondrial proteins. Mechanistically, Gal-1 silencing resulted in increased foam cell formation and mitochondrial dysfunction in VSMCs, while treatment with recombinant Gal-1 (rGal-1) prevented these effects. Furthermore, rGal-1 treatment attenuated atherosclerosis and elastase-induced AAA, leading to higher contractile VSMCs in aortic tissues. Gal-1 expression decreased in human atheroma and AAA compared to control tissue. Thus, Gal-1-driven circuits emerge as potential therapeutic strategies in atherosclerosis and AAA.


Assuntos
Aneurisma da Aorta Abdominal , Aterosclerose , Animais , Aneurisma da Aorta Abdominal/etiologia , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Aterosclerose/genética , Aterosclerose/metabolismo , Modelos Animais de Doenças , Galectina 1/genética , Galectina 1/metabolismo , Galectina 1/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Proteômica , Remodelação Vascular
7.
Biomolecules ; 12(2)2022 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-35204706

RESUMO

Abdominal aortic aneurysm (AAA) is a potentially fatal vascular disease that involves complex multifactorial hemodynamic, thrombotic, inflammatory, and aortic wall remodeling processes. However, its mechanisms are incompletely understood. It has become increasingly clear that platelets are involved in pathological processes of vascular diseases beyond their role in hemostasis and thrombosis. Platelet activation with membrane receptors and secreted mediators promotes thrombus formation and the accumulation of inflammatory cells, which may play an important role in the development of AAA by destroying the structural integrity and stability of the vessel wall. Turbulent blood flow in aortic aneurysms promotes platelet activation and aggregation. Platelet count and heterogeneity are important predictive, diagnostic, and prognostic indicators of AAA. We summarize the relationship between platelet activation and AAA development and propose future research directions and possible clinical applications.


Assuntos
Aneurisma da Aorta Abdominal , Trombose , Aorta/patologia , Aneurisma da Aorta Abdominal/patologia , Plaquetas/patologia , Humanos , Ativação Plaquetária , Trombose/patologia
8.
Biomolecules ; 12(2)2022 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-35204755

RESUMO

An intraluminal thrombus (ILT), which accumulates large numbers of neutrophils, plays a key role in abdominal aortic aneurysm (AAA) pathogenesis. This study aimed to compare levels of selected neutrophil inflammatory mediators in thick and thin ILT, plus adjacent AAA walls, to determine whether levels depend on ILT thickness. Neutrophil mediator levels were analysed by enzyme-linked immunosorbent assays in thick and thin segments of ILT, plus adjacent aneurysm wall sections, taken from one aneurysm sac each from 36 AAA patients. In aneurysmal walls covered by thick ILT, neutrophil elastase and TNF-a levels were significantly higher, as were concentrations of IL-6, in thick ILT compared to thin layers. Positive correlations of NGAL, MPO, and neutrophil elastase were observed between thick ILT and the adjacent wall and thin ILT and the adjacent wall, suggesting that these mediators probably infiltrate thick AAA compartments as well as thin. These observations might support the idea that neutrophil mediators and inflammatory cytokines differentially accumulate in AAA tissues according to ILT thickness. The increased levels of neutrophil mediators within thicker AAA segments might suggest the existence of an intensified proinflammatory state that in turn presumably might preferentially weaken the AAA wall at that region.


Assuntos
Aneurisma da Aorta Abdominal , Trombose , Aneurisma da Aorta Abdominal/patologia , Humanos , Neutrófilos/patologia , Trombose/patologia
9.
Phytother Res ; 36(2): 928-937, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35132703

RESUMO

Abdominal aortic aneurysm (AAA) is a lethal disease without available medicine for treatment. This study aimed to evaluate the efficiency of eugenol (4-allyl-2-methoxyphenol) against AAA and the underlying mechanism. Eugenol is the major bioactive component of clove. A mouse AAA model was established through porcine pancreatic elastase (PPE) incubation peri-adventitially and 1% 3-aminopropanonitrile (BAPN) diet. Continuous AAA progression from day 0 to day 15 was observed after PPE plus BAPN treatment, according to the AAA diameter and histopathological evaluation. Accompanying with AAA progression, sustained increased expressions of CD68, COX-2 and NF-κB were observed through immunofluorescence assay. After elucidation the efficiency of eugenol against AAA progression by AAA diameter, hematoxylin-eosin staining and orcein staining, the down-regulations of eugenol on COX-2 and NF-κB were further detected by immunohistochemistry and western blot. Eugenol not only blocked AAA expansion and protected the integrity of aortic structure in a dose-dependent manner, but also held high oral bioavailability. Excellent efficiency, high oral bioavailability and down-regulation on COX-2/NF-κB endowed eugenol great potential for future AAA therapy.


Assuntos
Aneurisma da Aorta Abdominal , Animais , Aneurisma da Aorta Abdominal/tratamento farmacológico , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Regulação para Baixo , Eugenol/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Suínos
10.
PLoS One ; 17(2): e0264327, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35202427

RESUMO

OBJECTIVES: A growing number of abdominal aortic aneurysms with severe angulated neck anatomy is treated by endovascular means. However, contradictory early and late outcomes have been reported. Our review and outcome analysis attempted to evaluate the available literature and provide clinicians with a base for clinical implementation and future research. MATERIALS AND METHODS: A systematic review of the literature was undertaken to identify the outcomes of endovascular aneurysm repair in patients with severe infrarenal neck angulation (SNA ≥ 60°) vs non-severe neck angulation (NSNA). Outcome measures included perioperative complications, type 1a endoleak, neck-related secondary procedures, stent graft migration, aneurysm rupture, increase (>5mm) in sac diameter, all-cause and aneurysm-related mortality (PROSPERO Nr.: CRD42021233253). RESULTS: Six observational studies reporting on 5981 patients (1457 with SNA and 4524 with NSNA) with a weighted mean follow-up period of 1.8 years were included. EVAR in SNA compared with NSNA was associated with a higher rate of type 1a endoleak at 30 days (4.0% vs 1.8%; p< 0.00001), at 1 year (2.8% vs 1.9%; p<0.03), at 2 years (4.9% vs 2.1%; p< 0.0002), at 3 years (5.6% vs 2.6%; p< 0.0001). The rate of neck-related secondary procedures was significantly higher at 1 year (6.6% vs 3.9%; p<0.05) and at 3 years (13.1% vs 9%; p<0.05). Graft migration, aneurysm sack increase, aneurysm rupture and all-cause mortality were not statistically different at mid-term. CONCLUSIONS: The use of EVAR in severely angulated infrarenal aortic necks is associated with a high rate of early and mid-term complications. However, aortic related and all-causes mortality are not higher compared to patients with NSNA. Therefore, EVAR should be cautiously used in patients with SNA.


Assuntos
Aneurisma da Aorta Abdominal/cirurgia , Procedimentos Endovasculares , Aneurisma da Aorta Abdominal/mortalidade , Aneurisma da Aorta Abdominal/patologia , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/mortalidade , Humanos , Complicações Pós-Operatórias , Resultado do Tratamento
11.
J Vis Exp ; (180)2022 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-35225256

RESUMO

Abdominal aortic aneurysm (AAA), although primarily asymptomatic, is potentially life-threatening as the rupture of AAA usually has a devastating outcome. Currently, there are several distinct experimental models of AAA, each emphasizing a different aspect in the pathogenesis of AAA. The elastase-induced AAA model is the second most used rodent AAA model. This model involves direct infusion or application of porcine pancreatic elastase (PPE) to the infrarenal segment of the aorta. Due to technical challenges, most elastase-induced AAA model nowadays is performed with the external application rather than an intraluminal infusion of PPE. The infiltration of elastase will cause degradation of elastic lamellae in the medial layers, resulting in the loss of aortic wall integrity and subsequent dilation of the abdominal aorta. However, one disadvantage of the elastase-induced AAA model is the inevitable variation of how the surgery is performed. Specifically, the surgical technique of isolating the infrarenal segment of the aorta, the material used for aorta wrapping and PPE incubation, the enzymatic activity of PPE, and the time duration of PPE application can all be important determinants that affect the eventual AAA formation rate and aneurysm diameter. Notably, the difference in these factors from different studies on AAA can lead to reproducibility issues. This article describes a detailed surgical process of the elastase-induced AAA model through direct application of PPE to the adventitia of the infrarenal abdominal aorta in the mouse. Following this procedure, a stable AAA formation rate of around 80% in male and female mice is achievable. The consistency and reproducibility of AAA studies using an elastase-induced AAA model can be significantly enhanced by establishing a standard surgical procedure.


Assuntos
Aneurisma da Aorta Abdominal , Elastase Pancreática , Animais , Aorta Abdominal/patologia , Aorta Abdominal/cirurgia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/patologia , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Elastase Pancreática/metabolismo , Reprodutibilidade dos Testes , Suínos
12.
Biomolecules ; 12(2)2022 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-35204673

RESUMO

Abdominal aortic aneurysm (AAA) is a life-threatening disease associated with high morbidity and mortality in the setting of acute rupture. Recently, advances in surgical and endovascular repair of AAA have been achieved; however, pharmaceutical therapies to prevent AAA expansion and rupture remain lacking. This highlights an ongoing need to improve the understanding the pathological mechanisms that initiate formation, maintain growth, and promote rupture of AAA. Over the past decade, epigenetic modifications, such as DNA methylation, posttranslational histone modifications, and non-coding RNA, have emerged as important regulators of cellular function. Accumulating studies reveal the importance of epigenetic enzymes in the dynamic regulation of key signaling pathways that alter cellular phenotypes and have emerged as major intracellular players in a wide range of biological processes. In this review, we discuss the roles and implications of epigenetic modifications in AAA animal models and their relevance to human AAA pathology.


Assuntos
Aneurisma da Aorta Abdominal , Animais , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/patologia , Metilação de DNA , Epigênese Genética
13.
Inflammation ; 45(3): 965-976, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35076833

RESUMO

The role of inflammation in the development of aortic aneurysms is emerging, along with the potential diagnostic and therapeutical potential of this correlation. Abdominal aorta aneurysms have a strong inflammatory substrate since atherosclerosis, which is undoubtedly linked to inflammation, is also a predisposing factor to their formation. Yet, data have emerged that the development of thoracic aorta aneurysms involves several inflammatory pathways, although they were previously referred to as a non-inflammatory disease. Since aortic aneurysms are mainly asymptomatic during their clinical course until their complications-which may be lethal-serum biomarkers for their early diagnosis are a necessity. Studies highlight that inflammation molecules may have a critical role in that direction. In addition, imaging techniques that trace aortic wall inflammation are developed in order to predict aneurysm growth rates and sites vulnerable of rupture. Several anti-inflammatory agents have been also studied in animal models and clinical trials for the treatment of aortic aneurysms. This review highlights the role of inflammation in pathogenesis, diagnosis and treatment of aortic aneurysms.


Assuntos
Aneurisma da Aorta Abdominal , Aneurisma da Aorta Torácica , Aneurisma Aórtico , Animais , Anti-Inflamatórios , Aorta , Aneurisma Aórtico/diagnóstico , Aneurisma Aórtico/terapia , Aneurisma da Aorta Abdominal/diagnóstico , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/terapia , Aneurisma da Aorta Torácica/diagnóstico , Aneurisma da Aorta Torácica/patologia , Inflamação/diagnóstico
14.
Comput Math Methods Med ; 2022: 3200798, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35035519

RESUMO

BACKGROUND: Data mining of current gene expression databases has not been previously performed to determine whether sirtuin 6 (SIRT6) expression participates in the pathological process of abdominal aortic aneurysm (AAA). The present study was aimed at investigating the role and mechanism of SIRT6 in regulating phenotype transformation of vascular smooth muscle cells (VSMC) in AAA. METHODS: Three gene expression microarray datasets of AAA patients in the Gene Expression Omnibus (GEO) database and one dataset of SIRT6-knockout (KO) mice were selected, and the differentially expressed genes (DEGs) were identified using GEO2R. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of both the AAA-related DEGs and the SIRT6-related DEGs were conducted. RESULTS: GEO2R analysis showed that the expression of SIRT6 was downregulated for three groups and upregulated for one group in the three datasets, and none of them satisfied statistical significance. There were top 5 DEGs (KYNU, NPTX2, SCRG1, GRK5, and RGS5) in both of the human AAA group and SIRT6-KO mouse group. Top 25 ontology of the SIRT6-KO-related DEGs showed that several pathways including tryptophan catabolic process to kynurenine and negative regulation of cell growth were enriched in the tissues of thickness aortic wall biopsies of AAA patients. CONCLUSIONS: Although SIRT6 mRNA level itself did not change among AAA patients, SIRT6 may play an important role in regulating several signaling pathways with significant association with AAA, suggesting that SIRT6 mRNA upregulation is a protective factor for VSMC against AAA.


Assuntos
Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/metabolismo , Miócitos de Músculo Liso/metabolismo , Sirtuínas/genética , Sirtuínas/metabolismo , Animais , Aneurisma da Aorta Abdominal/patologia , Biologia Computacional , Bases de Dados Genéticas/estatística & dados numéricos , Regulação para Baixo , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Masculino , Camundongos , Camundongos Knockout , Miócitos de Músculo Liso/patologia , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/genética , Sirtuínas/deficiência , Regulação para Cima
15.
Arterioscler Thromb Vasc Biol ; 42(3): 277-288, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35045728

RESUMO

AngII (angiotensin II) infusion in mice has been used to provide mechanistic insight into human abdominal aortic aneurysms for over 2 decades. This is a technically facile animal model that recapitulates multiple facets of the human disease. Although numerous publications have reported abdominal aortic aneurysms with AngII infusion in mice, there remain many fundamental unanswered questions such as uniformity of describing the pathological characteristics and which cell type is stimulated by AngII to promote abdominal aortic aneurysms. Extrapolation of the findings to provide insight into the human disease has been hindered by the preponderance of studies designed to determine the effects on initiation of abdominal aortic aneurysms, rather than a more clinically relevant scenario of determining efficacy on the established disease. The purpose of this review is to enhance understanding of AngII-induced abdominal aortic pathologies in mice, thereby providing greater insight into the human disease.


Assuntos
Angiotensina II/toxicidade , Aneurisma da Aorta Abdominal/etiologia , Fatores Etários , Angiotensina II/administração & dosagem , Animais , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/terapia , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Hipercolesterolemia/complicações , Masculino , Camundongos , Camundongos Transgênicos , Modelos Cardiovasculares , Receptores de Angiotensina/efeitos dos fármacos , Fatores Sexuais
16.
Sci Rep ; 12(1): 99, 2022 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-34997075

RESUMO

Abdominal aortic aneurysm (AAA) formation and expansion is highly complex and multifactorial, and the improvement of animal models is an important step to enhance our understanding of AAA pathophysiology. In this study, we explore our ability to influence aneurysm growth in a topical elastase plus ß-Aminopropionitrile (BAPN) mouse model by varying elastase concentration and by altering the cross-linking capability of the tissue. To do so, we assess both chronic and acute effects of elastase concentration using volumetric ultrasound. Our results suggest that the applied elastase concentration affects initial elastin degradation, as well as long-term vessel expansion. Additionally, we assessed the effects of BAPN by (1) removing it to restore the cross-linking capability of tissue after aneurysm formation and (2) adding it to animals with stable aneurysms to interrupt cross-linking. These results demonstrate that, even after aneurysm formation, lysyl oxidase inhibition remains necessary for continued expansion. Removing BAPN reduces the aneurysm growth rate to near zero, resulting in a stable aneurysm. In contrast, adding BAPN causes a stable aneurysm to expand. Altogether, these results demonstrate the ability of elastase concentration and BAPN to modulate aneurysm growth rate and severity. The findings open several new areas of investigation in a murine model that mimics many aspects of human AAA.


Assuntos
Aminopropionitrilo , Aorta Abdominal/enzimologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Elastase Pancreática , Proteína-Lisina 6-Oxidase/antagonistas & inibidores , Administração Tópica , Animais , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/enzimologia , Aneurisma da Aorta Abdominal/patologia , Dilatação Patológica , Modelos Animais de Doenças , Progressão da Doença , Feminino , Masculino , Camundongos Endogâmicos C57BL , Proteína-Lisina 6-Oxidase/metabolismo , Índice de Gravidade de Doença
17.
Ann Vasc Surg ; 79: 290-297, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34648852

RESUMO

BACKGROUND: We aimed to investigate the formation and self-healing process of rabbit abdominal aortic aneurysm (AAA) by focus on the degeneration and regeneration of smooth muscle cells (SMCs) in elastase-induced AAA model and enlarging AAA model in rabbits. METHODS: Sixty rabbits were equally divided into 2 aneurysm groups (Group A and Group B). Rabbits received a 10-min incubation of elastase in Group A (10 units/µL) and Group B (1 unit/µL). Rabbits underwent aortic stenosis above the incubated segment in Group B. Aortic diameter was measured and rabbits were sacrificed for histopathological and immunohistochemical studies. RESULTS: The incubated aorta dilated immediately and ran up to maxima by day 21 in Group A. All aneurysms formed by day 21 and enlarged progressively in Group B. SMCs content, elastin content and intima-media thickness decreased significantly by day 0 in Group A. SMCs and elastic fibers were destroyed gradually in Group B, however, SMCs content was significantly lower than Group A by day 70. Intimal thickness increased significantly by day 70 in the Aneurysm groups. MMP2 maintained moderate expression in Group A, which decreased significantly by day 3 in Group B. MMP9 and RAM11 expressions were higher by day 1, but decreased significantly by day 3 in Group B. CONCLUSIONS: Irreversible degeneration of SMCs is critical to a rapid formation of elastase-induced rabbit AAA model, and SMCs excessive regeneration accounts for the selfhealing process. SMCs degradation and regeneration remain relatively stable in an enlarging AAA model. SMCs should be the key target for studying the mechanism of AAA and intervention therapy.


Assuntos
Aneurisma da Aorta Abdominal/patologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Regeneração , Remodelação Vascular , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aorta Abdominal/fisiopatologia , Aorta Abdominal/cirurgia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/fisiopatologia , Dilatação Patológica , Modelos Animais de Doenças , Tecido Elástico/metabolismo , Tecido Elástico/patologia , Elastina/metabolismo , Ligadura , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/metabolismo , Elastase Pancreática , Coelhos , Fatores de Tempo
18.
Free Radic Biol Med ; 178: 111-124, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34863875

RESUMO

Inflammation has recently emerged as an important contributor for cardiovascular disease development and participates pivotally in the development of neointimal hyperplasia and abdominal aortic aneurysms (AAA) formation. Kv7.4/KCNQ4, a K+ channel, is one of the important regulators of vascular function but its role in vascular inflammation is unexplored. Here, we showed that the expression of Kv7.4 channel was elevated in the neointima and AAA tissues from mice and humans. Genetic deletion or pharmacological inhibition of Kv7.4 channel in mice alleviated neointimal hyperplasia and AAA formation via downregulation of a set of vascular inflammation-related genes, matrix metalloproteinases (MMP) 2/9, and intercellular adhesion molecule (ICAM-1). Furthermore, genetic deletion or inhibition of Kv7.4 channel suppressed the activation of tumor necrosis factor receptor 1 (TNFR1)-nuclear factor (NF)-κB signaling pathway via blockade of interaction between TNFR1 and TNFR1-associated death domain protein (TRADD) in vascular smooth muscle cells (VSMCs). Knockdown of Kv7.4 in vivo identified VSMC-expressed Kv7.4 as a major factor in vascular inflammation. Collectively, our findings suggest that Kv7.4 channel aggravates vascular inflammatory response, which promotes the neointimal hyperplasia and AAA formation. Inhibition of Kv7.4 channel may be a novel therapeutic strategy for vascular inflammatory diseases.


Assuntos
Aneurisma da Aorta Abdominal , Neointima , Animais , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/patologia , Movimento Celular , Proliferação de Células , Células Cultivadas , Hiperplasia/patologia , Inflamação/genética , Inflamação/patologia , Camundongos , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Neointima/patologia , Remodelação Vascular
19.
Microvasc Res ; 140: 104280, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34856183

RESUMO

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.


Assuntos
Anti-Inflamatórios/farmacologia , Aneurisma da Aorta Abdominal/prevenção & controle , Plasticidade Celular/efeitos dos fármacos , Inflamassomos/antagonistas & inibidores , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Oligopeptídeos/farmacologia , Animais , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/imunologia , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/imunologia , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Inflamassomos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/imunologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/imunologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fenótipo , Transdução de Sinais , Remodelação Vascular/efeitos dos fármacos
20.
Br J Surg ; 109(2): 211-219, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34849588

RESUMO

BACKGROUND: The most relevant determinant in scheduling monitoring intervals for abdominal aortic aneurysms (AAAs) is maximum diameter. The aim of the study was to develop a statistical model that takes into account specific characteristics of AAA growth distributions such as between-patient variability as well as within-patient variability across time, and allows probabilistic statements to be made regarding expected AAA growth. METHODS: CT angiography (CTA) data from patients monitored at 6-month intervals with maximum AAA diameters at baseline between 30 and 66 mm were used to develop the model. By extending the model of geometric Brownian motion with a log-normal random effect, a stochastic growth model was developed. An additional set of ultrasound-based growth data was used for external validation. RESULTS: The study data included 363 CTAs from 87 patients, and the external validation set comprised 390 patients. Internal and external cross-validation showed that the stochastic growth model allowed accurate description of the distribution of aneurysm growth. Median relative growth within 1 year was 4.1 (5-95 per cent quantile 0.5-13.3) per cent. Model calculations further resulted in relative 1-year growth of 7.0 (1.0-16.4) per cent for patients with previously observed rapid 1-year growth of 10 per cent, and 2.6 (0.3-8.3) per cent for those with previously observed slow growth of 1 per cent. The probability of exceeding a threshold of 55 mm was calculated to be 1.78 per cent at most when adhering to the current RESCAN guidelines for rescreening intervals. An online calculator based on the fitted model was made available. CONCLUSION: The stochastic growth model was found to provide a reliable tool for predicting AAA growth.


Assuntos
Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/patologia , Modelos Estatísticos , Idoso , Angiografia por Tomografia Computadorizada , Progressão da Doença , Feminino , Humanos , Masculino , Prognóstico , Fatores de Risco , Processos Estocásticos , Fatores de Tempo
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