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1.
Arterioscler Thromb Vasc Biol ; 41(3): 1158-1166, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33472403

RESUMO

OBJECTIVE: Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease characterized by smooth muscle cell depletion, ECM (extracellular matrix) degradation, and infiltration of immune cells. The cellular and molecular profiles that govern the heterogeneity of the AAA aorta are yet to be elucidated. Approach and Results: We performed single-cell RNA sequencing on mouse AAA tissues. AAA was induced in C57BL/6J mice by perivascular application of CaCl2. Unbiased clustering identified 12 distinct populations of 8 cell types. Percentages of each population and gene expression were compared between sham and AAA tissue. Furthermore, we characterized the transcriptional profiles and potential functional features of populations in smooth muscle cells, fibroblasts, and macrophages and revealed the unique regulons in each cell type. CONCLUSIONS: Together, these data provide high-resolution insight into the complexity and heterogeneity of mouse AAA and indicate that populations within major cell types such as smooth muscle cells, fibroblasts, and macrophages may contribute differently to AAA pathogenesis. Graphic Abstract: A graphic abstract is available for this article.


Assuntos
Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/patologia , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/etiologia , Proliferação de Células , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fibroblastos/patologia , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , RNA-Seq , Análise de Célula Única
2.
Int J Mol Sci ; 22(2)2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33429925

RESUMO

Neutrophils are primary effector cells of innate immunity and fight infection by phagocytosis and degranulation. Activated neutrophils also release neutrophil extracellular traps (NETs) in response to a variety of stimuli. These NETs are net-like complexes composed of cell-free DNA, histones and neutrophil granule proteins. Besides the evolutionarily conserved mechanism to capture and eliminate pathogens, NETs are also associated with pathophysiological processes of various diseases. Here, we elucidate the mechanisms of NET formation and their different implications in disease. We focused on autoinflammatory and cardiovascular disorders as the leading cause of death. Neutrophil extracellular traps are not only present in various cardiovascular diseases but play an essential role in atherosclerotic plaque formation, arterial and venous thrombosis, as well as in the development and progression of abdominal aortic aneurysms. Furthermore, NETosis can be considered as a source of autoantigens and maintains an inflammatory milieu promoting autoimmune diseases. Indeed, there is further need for research into the balance between NET induction, inhibition, and degradation in order to pharmacologically target NETs and their compounds without impairing the patient's immune defense. This review may be of interest to both basic scientists and clinicians to stimulate translational research and innovative clinical approaches.


Assuntos
Doenças Autoimunes/imunologia , Armadilhas Extracelulares/imunologia , Neutrófilos/imunologia , Aneurisma da Aorta Abdominal/patologia , Doenças Autoimunes/patologia , Autoimunidade/imunologia , /patologia , Humanos , Ativação de Neutrófilo/imunologia , Placa Aterosclerótica/patologia , Trombose/patologia
3.
Arch Biochem Biophys ; 698: 108724, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33309615

RESUMO

Abdominal aortic aneurysm (AAA) is a fatal vascular disease with insidious symptoms. However, the mechanism behind its development remains unclear. The transient receptor potential vanilloid (TRPV) family has crucial protective effects against cardiovascular diseases, but the role of TRPV5 in AAA has yet to be reported. In this study, ApoE-/- mice were intraperitoneally injected with AAV-GFP or AAV-TRPV5. After 30 days, mice were further administered with angiotensin II (Ang II, 1.44 mg/kg/day) by using osmotic pumps to induce the AAA model or Saline for 28 days, (i.e., Saline + AAV-GFP, Saline + AAV-TRPV5, Ang II + AAV-GFP and Ang II + AAV-TRPV5 groups were established). Compared with the control group, the incidence of AAA and the maximal diameter of the abdominal aorta markedly decreased in Ang II + AAV-TRPV5, which was detected by vascular ultrasound at 28 day. Meanwhile, less collagen and elastin degradation were observed in the Ang II + AAV-TRPV5 group by using Masson and Elastin stains. Moreover, more α-SMA and less MMP2 was observed in the abdominal aortas collected at 28 day by immunohistochemistry. In vitro, primary mouse vascular smooth muscle cells (VSMCs) were treated with Ang II (1 µM) to induce phenotype switch. Sh-TRPV5 and AdTRPV5 were used to transfect VSMCs. PCR and Western blotting were used to access the expression of contractile marker, including α-SMA and SM-22α. The results showed that the mRNA and protein level of α-SMA and SM-22α were decreased under the stimulation of Ang II, but could be attenuated by TRPV5 overexpression. The cell scratch assay demonstrated that the migration ability of VSMCs was increased in Ang II treated group and could be ameliorated by TRPV5 overexpression. Above all, VSMCs transformed from the contractile into secretory phenotype under Ang II stimuli, but could be rescued by TRPV5 overexpression. Furthermore, TRPV5 overexpression suppressed the increased expression of KLF4 induced by Ang II treatment in VSMCs. The data demonstrated that TRPV5 could inhibit AAA formation and play a critical role in the VSMC phenotype switch by downregulating KLF4, suggesting TRPV5 as a new strategy for treating AAA.


Assuntos
Aneurisma da Aorta Abdominal/tratamento farmacológico , Canais de Cálcio/farmacologia , Fatores de Transcrição Kruppel-Like/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Canais de Cátion TRPV/farmacologia , Angiotensina II , Animais , Aorta/citologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/patologia , Canais de Cálcio/genética , Diferenciação Celular/efeitos dos fármacos , Dependovirus/genética , Regulação para Baixo , Técnicas de Transferência de Genes , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Canais de Cátion TRPV/genética , Regulação para Cima
5.
PLoS Biol ; 18(8): e3000808, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32817651

RESUMO

Although dysregulation of mitochondrial dynamics has been linked to cellular senescence, which contributes to advanced age-related disorders, it is unclear how Krüppel-like factor 5 (Klf5), an essential transcriptional factor of cardiovascular remodeling, mediates the link between mitochondrial dynamics and vascular smooth muscle cell (VSMC) senescence. Here, we show that Klf5 down-regulation in VSMCs is correlated with rupture of abdominal aortic aneurysm (AAA), an age-related vascular disease. Mice lacking Klf5 in VSMCs exacerbate vascular senescence and progression of angiotensin II (Ang II)-induced AAA by facilitating reactive oxygen species (ROS) formation. Klf5 knockdown enhances, while Klf5 overexpression suppresses mitochondrial fission. Mechanistically, Klf5 activates eukaryotic translation initiation factor 5a (eIF5a) transcription through binding to the promoter of eIF5a, which in turn preserves mitochondrial integrity by interacting with mitofusin 1 (Mfn1). Accordingly, decreased expression of eIF5a elicited by Klf5 down-regulation leads to mitochondrial fission and excessive ROS production. Inhibition of mitochondrial fission decreases ROS production and VSMC senescence. Our studies provide a potential therapeutic target for age-related vascular disorders.


Assuntos
Aneurisma da Aorta Abdominal/genética , Células Endoteliais/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Mitocôndrias/metabolismo , Fatores de Iniciação de Peptídeos/genética , Proteínas de Ligação a RNA/genética , Idoso , Angiotensina II/genética , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Animais , Aorta/diagnóstico por imagem , Aorta/metabolismo , Aorta/patologia , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Senescência Celular/efeitos dos fármacos , Ecocardiografia , Células Endoteliais/patologia , Feminino , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Humanos , Fatores de Transcrição Kruppel-Like/deficiência , Masculino , Camundongos , Camundongos Knockout , Mitocôndrias/patologia , Dinâmica Mitocondrial/efeitos dos fármacos , Fatores de Iniciação de Peptídeos/deficiência , Cultura Primária de Células , Regiões Promotoras Genéticas , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismo
6.
Arterioscler Thromb Vasc Biol ; 40(10): 2494-2507, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32787523

RESUMO

OBJECTIVE: Currently, there are no approved drugs for abdominal aortic aneurysm (AAA) treatment, likely due to limited understanding of the primary molecular mechanisms underlying AAA development and progression. BAF60a-a unique subunit of the SWI/SNF (switch/sucrose nonfermentable) chromatin remodeling complex-is a novel regulator of metabolic homeostasis, yet little is known about its function in the vasculature and pathogenesis of AAA. In this study, we sought to investigate the role and underlying mechanisms of vascular smooth muscle cell (VSMC)-specific BAF60a in AAA formation. Approach and Results: BAF60a is upregulated in human and experimental murine AAA lesions. In vivo studies revealed that VSMC-specific knockout of BAF60a protected mice from both Ang II (angiotensin II)-induced and elastase-induced AAA formation with significant suppression of vascular inflammation, monocyte infiltration, and elastin fragmentation. Through RNA sequencing and pathway analysis, we found that the expression of inflammatory response genes in cultured human aortic smooth muscle cells was significantly downregulated by small interfering RNA-mediated BAF60a knockdown while upregulated upon adenovirus-mediated BAF60a overexpression. BAF60a regulates VSMC inflammation by recruiting BRG1 (Brahma-related gene-1)-a catalytic subunit of the SWI/SNF complex-to the promoter region of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) target genes. Furthermore, loss of BAF60a in VSMCs prevented the upregulation of the proteolytic enzyme cysteine protease CTSS (cathepsin S), thus ameliorating ECM (extracellular matrix) degradation within the vascular wall in AAA. CONCLUSIONS: Our study demonstrated that BAF60a is required to recruit the SWI/SNF complex to facilitate the epigenetic regulation of VSMC inflammation, which may serve as a potential therapeutic target in preventing and treating AAA.


Assuntos
Aneurisma da Aorta Abdominal/prevenção & controle , Aortite/prevenção & controle , Proteínas Cromossômicas não Histona/deficiência , Matriz Extracelular/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Remodelação Vascular , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Aortite/genética , Aortite/metabolismo , Aortite/patologia , Estudos de Casos e Controles , Catepsinas/metabolismo , Células Cultivadas , Proteínas Cromossômicas não Histona/genética , Modelos Animais de Doenças , Matriz Extracelular/patologia , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Transdução de Sinais
7.
Gene ; 762: 145056, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32805313

RESUMO

BACKGROUND: Abdominal aortic aneurysm (AAA) is a disease characterized by weakening arterial wall and permanent expansion with high mortality once rupture, which was involved with immune system activation. However, owing to technical difficulties, previous research has limited the impact of one or limited immune cells on AAA. METHODS: We analyzed the composition of immune cells using the CIBERSORT algorithm through transcriptome sequencing data from patients with stable (eAAA) and ruptured aneurysms (rAAA). The whole transcriptome sequencing data, including 17 patients with ruptured AAA and 31 patients with stable AAA were downloaded from Gene Expression Omnibus (GEO, GSE98278). After normalizing and data processing, five rAAA and seventeen eAAA patients entered the follow-up analysis. We performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis to identify several pathways that were significantly enriched in rAAA compared to eAAA tissues. RESULTS: We demonstrated that the compositions of infiltrative immune cell in eAAA and rAAA were different. Naïve B cells, both resting and activated CD4+ memory T cells were found significantly higher in ruptured AAA, while memory B cells and activated mast cells were much less in ruptured AAA than that in stable AAA. Besides, PTX3 was significantly highly expressed in rAAA, which might be associated with the complement system and polarization of macrophages. Finally, differentially expressed genes and the related immune cells were mapped in a network to reveal the relationship between gene expression and infiltrative immune cells. CONCLUSION: We identified the infiltrated immune cell profile of eAAA and rAAA patients, which might be the potential target of AAA treatment.


Assuntos
Aneurisma da Aorta Abdominal/genética , Ruptura Aórtica/genética , Linfócitos B/metabolismo , Linfócitos T/metabolismo , Transcriptoma , Animais , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Ruptura Aórtica/metabolismo , Ruptura Aórtica/patologia , Proteína C-Reativa/genética , Proteína C-Reativa/metabolismo , Células Dendríticas/metabolismo , Humanos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Componente Amiloide P Sérico/genética , Componente Amiloide P Sérico/metabolismo
8.
Eur J Vasc Endovasc Surg ; 60(5): 671-676, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32807677

RESUMO

OBJECTIVE: The aim of this study was to measure the incidence of post endovascular aneurysm sealing (EVAS) abdominal aortic aneurysm (AAA) growth, and its association with stent migration, in a cohort of patients with differing compliance to old and new Instructions For Use (IFU). METHODS: A retrospective single centre study was conducted to review the computed tomography (CT) and clinical data of elective, infrarenal EVAS cases, performed as a primary intervention, between December 2013 and March 2018. All included patients had a baseline post-operative CT scan at one month and at least one year follow up. The primary outcome measure was the incidence of AAA growth and its association with stent migration. AAA growth was defined as a ≥5% increase in aortic volume between the lowermost renal artery and the aortic bifurcation post EVAS at any time during follow up, in comparison to the baseline CT scan. Migration was defined according to the ESVS guidelines, as > 10 mm downward movement of either Nellix stent frame in the proximal zone. RESULTS: Seventy-six patients were eligible for inclusion in the study (mean age 76 ± 7.4 years; 58 men). AAA growth was identified in 50 of 76 patients (66%); adherence to IFU did not affect its incidence (mean growth within IFU-2016 compliant cohort vs. non-compliant: 16% vs. 13%, p = .33). Over time, the incidence of AAA growth increased, from 32% at one year to 100% at four years. AAA growth by volume was progressive (p < .001), as its extent increased over time. Migration was detected in 16 patients and there was a statistically significant association with AAA growth (13 patients displayed migration and AAA growth, p = .036). CONCLUSION: Patients treated with EVAS are prone to AAA growth, irrespective of whether their aortic anatomy is IFU compliant. AAA growth by volume is associated with stent migration. Clinicians should continue close surveillance post EVAS, regardless of whether patients are treated within IFU.


Assuntos
Aneurisma da Aorta Abdominal/cirurgia , Implante de Prótese Vascular/efeitos adversos , Procedimentos Cirúrgicos Eletivos/efeitos adversos , Procedimentos Endovasculares/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Falha de Prótese , Idoso , Idoso de 80 Anos ou mais , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/patologia , Aorta Abdominal/cirurgia , Aneurisma da Aorta Abdominal/diagnóstico , Aneurisma da Aorta Abdominal/patologia , Prótese Vascular/efeitos adversos , Implante de Prótese Vascular/instrumentação , Progressão da Doença , Procedimentos Cirúrgicos Eletivos/instrumentação , Procedimentos Endovasculares/instrumentação , Feminino , Seguimentos , Humanos , Incidência , Masculino , Cooperação do Paciente , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Desenho de Prótese , Estudos Retrospectivos , Fatores de Risco , Stents/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
9.
Nat Commun ; 11(1): 4311, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32855420

RESUMO

Pulmonary disease increases the risk of developing abdominal aortic aneurysms (AAA). However, the mechanism underlying the pathological dialogue between the lungs and aorta is undefined. Here, we find that inflicting acute lung injury (ALI) to mice doubles their incidence of AAA and accelerates macrophage-driven proteolytic damage of the aortic wall. ALI-induced HMGB1 leaks and is captured by arterial macrophages thereby altering their mitochondrial metabolism through RIPK3. RIPK3 promotes mitochondrial fission leading to elevated oxidative stress via DRP1. This triggers MMP12 to lyse arterial matrix, thereby stimulating AAA. Administration of recombinant HMGB1 to WT, but not Ripk3-/- mice, recapitulates ALI-induced proteolytic collapse of arterial architecture. Deletion of RIPK3 in myeloid cells, DRP1 or MMP12 suppression in ALI-inflicted mice repress arterial stress and brake MMP12 release by transmural macrophages thereby maintaining a strengthened arterial framework refractory to AAA. Our results establish an inter-organ circuitry that alerts arterial macrophages to regulate vascular remodeling.


Assuntos
Lesão Pulmonar Aguda/complicações , Aneurisma da Aorta Abdominal/patologia , Proteína HMGB1/metabolismo , Macrófagos/metabolismo , Remodelação Vascular , Lesão Pulmonar Aguda/patologia , Animais , Aorta Abdominal/citologia , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/etiologia , Aneurisma da Aorta Abdominal/prevenção & controle , Células Cultivadas , Modelos Animais de Doenças , Dinaminas/antagonistas & inibidores , Dinaminas/metabolismo , Humanos , Macrófagos/citologia , Metaloproteinase 12 da Matriz/genética , Metaloproteinase 12 da Matriz/metabolismo , Camundongos , Camundongos Knockout , Dinâmica Mitocondrial/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Cultura Primária de Células , Proteólise/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/patologia , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Estudos Retrospectivos , Regulação para Cima
10.
PLoS One ; 15(8): e0234409, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32857766

RESUMO

BACKGROUND: An abdominal aortic aneurysm (AAA) is a progressive chronic dilatation of the abdominal aorta with terminally rupture when the aortic wall is so weakened that aortic wall stress exceeds wall strength. No effective medical treatment exists so far. We aimed to test whether intraluminal admission of Penta-Galloyl Glucose (PGG) treatment in a rodent AAA model could hold the potential to inhibit aneurysmal progression. METHOD: Male Sprague Dawley rats had either intraluminal elastase infused for AAA induction or saline to serve as controls. In two independent experimental series, elastase was used to induce AAA followed by an intraluminal PGG (directly or by a drug eluting balloon) treatment. All rats were followed for 28 days and euthanized. In both series, maximal infrarenal aortic diameter was measured at baseline and at termination as a measure of AAA size. In series 2, maximal internally AAA diameter was followed by ultrasound weekly. AAA tissues were analyzed for elastin integrity by millers stain, collagen deposition by masson trichrome staining. In other AAA tissue samples the mRNA level of CD45, lysyloxidase (LOX), lysyloxidase like protein 1 (LOXL1) were determined by qPCR. RESULTS: Direct administration of PGG significantly reduced AAA expansion when compared to controls. PGG treatment resulted in a higher number and more preserved elastic fibers in the aneurysmal wall, while no significant difference was seen in the levels of CD45 and LOX mRNA levels. The drug eluting balloon (DEB) experiment showed no significant difference in AAA size observed neither macroscopically nor ultrasonically. Also the aneurysmal mRNA levels of CD45, LOX and LOXL1 were unchanged between groups. CONCLUSION: A significant reduced expansion of AAAs was observed in the PGG group, suggesting PGG as a drug to inhibit aneurysmal progression, while administration through a DEB did not show a promising new way of administration.


Assuntos
Aneurisma da Aorta Abdominal/tratamento farmacológico , Taninos Hidrolisáveis/administração & dosagem , Animais , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Modelos Animais de Doenças , Progressão da Doença , Tecido Elástico/efeitos dos fármacos , Tecido Elástico/patologia , Infusões Intralesionais/instrumentação , Infusões Intralesionais/métodos , Masculino , Elastase Pancreática/administração & dosagem , Proteína-Lisina 6-Oxidase/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley
11.
J Cardiothorac Surg ; 15(1): 160, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32615991

RESUMO

BACKGROUND: To determine whether all-trans retinoic acid (ATRA) can influence the development of Angiotensin II (Ang II) induced experimental abdominal aortic aneurysms (AAAs). METHODS: Apolipoprotein E knock-out (ApoE-/-) mice were randomly assigned to 4 groups. Mice in the AAA and ATRA groups underwent continuous subcutaneous Ang II infusion for 28 days to induce AAA, while the Sham and Control groups were infused with saline. Systolic blood pressure was measured by the tail-cuff technique. The Control and ATRA groups received ATRA treatment. Aortic tissue samples were obtained at 28 days after surgery and evaluated by aortic diameter measurement, Western blotting, immunohistochemistry, and hematoxylin-eosin (H&E) and Verhoeff-Van Gieson (EVG) staining. RESULTS: The abdominal aortic diameter was significantly reduced in the ATRA group compared with the AAA group (3 of 12 (25%) vs 9 of 12 (75%), P < 0.05), and the ATRA group exhibited reduced blood pressure on days 7, 14, and 28. Low expression of angiotensin II receptor type 1 (AT1), matrix metalloproteinase 2 (MMP2), and matrix metalloproteinase 9 (MMP9) and EVG staining revealed a significant reduction in the disruption of elastic fibers in the abdominal aortic tissue of the ATRA group compared to the AAA group. Western blot analysis indicated that protein levels of retinoic acid receptor α (RARα), MMP2, MMP9, and AT1 were dramatically affected by ATRA treatment. CONCLUSIONS: In conclusion, ATRA attenuates the progression of Ang II-induced AAAs, possibly by downregulating MMP2, MMP9, and AT-1 expression.


Assuntos
Aneurisma da Aorta Abdominal/metabolismo , Tretinoína/farmacologia , Angiotensina II/metabolismo , Animais , Aneurisma da Aorta Abdominal/patologia , Modelos Animais de Doenças , Progressão da Doença , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Knockout para ApoE
12.
PLoS One ; 15(7): e0235553, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32614927

RESUMO

Aortic aneurysm refers to dilatation of the aorta due to loss of elasticity and degenerative weakening of its wall. A preventive role for osteoprotegerin (Opg) in the development of abdominal aortic aneurysm has been reported in the CaCl2-induced aneurysm model, whereas Opg was found to promote suprarenal aortic aneurysm in the AngII-induced ApoE knockout mouse aneurysm model. To determine whether there is a common underlying mechanism to explain the impact of Opg deficiency on the vascular structure of the two aneurysm models, we analyzed suprarenal aortic tissue of 6-month-old ApoE-/-Opg-/- mice after AngII infusion for 28 days. Less aortic dissection and aortic lumen dilatation, more adventitial thickening, and higher expression of collagen I and Trail were observed in ApoE-/-Opg-/- mice relative to ApoE-/-Opg+/+ mice. An accumulation of α-smooth muscle actin and vimentin double-positive myofibroblasts was noted in the thickened adventitia of ApoE-/-Opg-/- mice. Our results suggest that fibrotic remodeling of the aorta induced by myofibroblast accumulation might be an important pathological event which tends to limit AngII-induced aortic dilatation in ApoE -/-Opg-/- mice.


Assuntos
Túnica Adventícia/patologia , Aneurisma da Aorta Abdominal/patologia , Osteoprotegerina/genética , Túnica Adventícia/fisiologia , Angiotensina II/farmacologia , Animais , Aorta Abdominal/patologia , Aorta Abdominal/fisiologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Colesterol/sangue , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Fibrose , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miofibroblastos/citologia , Miofibroblastos/metabolismo , Osteoprotegerina/deficiência , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Regulação para Cima/efeitos dos fármacos
13.
Eur J Vasc Endovasc Surg ; 60(3): 452-460, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32703634

RESUMO

OBJECTIVE: Experimental studies suggest that fenofibrate prevents abdominal aortic aneurysm (AAA) development by lowering aortic osteopontin (OPN) concentration and reducing the number of macrophages infiltrating the aortic wall. The current study examined the effects of a short course of fenofibrate on AAA pathology in people with large AAAs awaiting aortic repair. METHODS: This randomised double blind parallel trial included male and female participants aged ≥ 60 years who had an asymptomatic AAA measuring ≥ 50 mm and were scheduled to undergo open AAA repair. Participants were allocated to fenofibrate (145 mg/day) or matching placebo for at least two weeks before elective AAA repair. Blood samples were collected at recruitment and immediately prior to surgery. AAA biopsies were obtained during aortic surgery. The primary outcomes were (1) AAA OPN concentration; (2) serum OPN concentration; and (3) number of AAA macrophages. Exploratory outcomes included circulating and aortic concentrations of other proteins previously associated with AAA. Outcomes assessed at a single time point were compared using logistic regression. Longitudinal outcomes were compared using linear mixed effects models. RESULTS: Forty-three participants were randomised. After three withdrawals, 40 were followed until the time of surgery (21 allocated fenofibrate and 19 allocated placebo). As expected, serum triglycerides reduced significantly from recruitment to the time of surgery in participants allocated fenofibrate. No differences in any of the primary and exploratory outcomes were observed between groups. CONCLUSION: A short course of 145 mg of fenofibrate/day did not lower concentrations of OPN or aortic macrophage density in people with large AAAs.


Assuntos
Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/cirurgia , Aneurisma da Aorta Abdominal/terapia , Fenofibrato/administração & dosagem , Procedimentos Cirúrgicos Vasculares , Idoso , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/sangue , Aneurisma da Aorta Abdominal/patologia , Biomarcadores/sangue , Progressão da Doença , Método Duplo-Cego , Esquema de Medicação , Feminino , Fenofibrato/efeitos adversos , Humanos , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Osteopontina/sangue , Queensland , Fatores de Tempo , Resultado do Tratamento , Triglicerídeos/sangue , Remodelação Vascular/efeitos dos fármacos , Procedimentos Cirúrgicos Vasculares/efeitos adversos
14.
Clin Sci (Lond) ; 134(12): 1555-1572, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32490531

RESUMO

Abdominal aortic aneurysm (AAA) is a localized pathological dilation of the aorta exceeding the normal diameter (∼20 mm) by more than 50% of its original size (≥30 mm), accounting for approximately 150000-200000 deaths worldwide per year. We previously reported that Notch inhibition does not decrease the size of pre-established AAA at late stage of the disease. Here, we examined whether a potent pharmacologic inhibitor of Notch signaling (DAPT (N-[N-(3,5-Difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester)), regresses an actively growing AAA. In a mouse model of an aneurysm (Apoe-/- mice; n=44); DAPT (n=17) or vehicle (n=17) was randomly administered at day 14 of angiotensin II (AngII; 1 µg/min/kg), three times a week and mice were killed on day 42. Progressive increase in aortic stiffness and maximal intraluminal diameter (MILD) was observed in the AngII + vehicle group, which was significantly prevented by DAPT (P<0.01). The regression of aneurysm with DAPT was associated with reduced F4/80+Cd68+ (cluster of differentiation 68) inflammatory macrophages. DAPT improved structural integrity of aorta by reducing collagen fibrils abnormality and restoring their diameter. Mechanistically, C-C chemokine receptor type 7 (Ccr7)+F4/80- dendritic cells (DCs), implicated in the regression of aneurysm, were increased in the aorta of DAPT-treated mice. In the macrophages stimulated with AngII or lipopolysaccharide (LPS), DAPT reverted the expression of pro-inflammatory genes Il6 and Il12 back to baseline within 6 h compared with vehicle (P<0.05). DAPT also significantly increased the expression of anti-inflammatory genes, including c-Myc, Egr2, and Arg1 at 12-24 h in the LPS-stimulated macrophages (P<0.05). Overall, these regressive effects of Notch signaling inhibitor emphasize its therapeutic implications to prevent the progression of active AAAs.


Assuntos
Aneurisma da Aorta Abdominal/tratamento farmacológico , Dipeptídeos/uso terapêutico , Receptores Notch/antagonistas & inibidores , Transdução de Sinais , Animais , Aorta/metabolismo , Aorta/patologia , Aneurisma da Aorta Abdominal/patologia , Apoptose , Citocinas/metabolismo , Células Dendríticas/metabolismo , Dipeptídeos/farmacologia , Progressão da Doença , Matriz Extracelular/metabolismo , Mediadores da Inflamação/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Fenótipo , Receptores Notch/metabolismo
15.
Ann Vasc Surg ; 69: 345-351, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32504789

RESUMO

BACKGROUND: Several studies in the literature report continued proximal aorta and distal iliac artery dilatation after surgical correction of an abdominal aortic aneurysm (AAA). The purpose of this study is to evaluate these findings, in a South American population, and relate them to the type of configuration of the open procedure aortic reconstruction. METHODS: This is a retrospective review of ultrasonographic follow-up of patients submitted to open repair of AAA from 1989 to 2013, reporting proximal aorta dilatation (≥3 cm) and distal iliac artery dilatation (≥1.5 cm). RESULTS: A total of 155 patients were included. Life-table freedom at the intervals 11 < 15 years and ≥15 years were 47% and 23% for proximal dilatation and 63% and 38% for distal iliac arteries dilatation, respectively. There were more proximal and distal dilatations in patients submitted to more extensive aortic reconstructions (aorto-aortic 13% and 22% vs aorto-bilateral common iliacs 27% and 8% vs aorto-unilateral or bilateral external iliacs 27% and 32% and aorto-femoral 67% and 0%) P < 0.0001. Juxtarenal anastomosis was also correlated with more proximal dilatations (42% vs 21%, P = 0,046). There were two proximal and three distal anastomosis pseudoaneurysms. CONCLUSIONS: The presence of more extensive degenerative disease at the time of operation, requiring juxtarenal or more distal iliac reconstructions, may pose an increased risk of proximal aorta and iliac artery dilatation during follow-up. This study corroborates that significant changes are found after 7 to 10 years of the operation, reinforcing the need for long-term monitoring.


Assuntos
Falso Aneurisma/patologia , Aorta Abdominal/cirurgia , Aneurisma da Aorta Abdominal/cirurgia , Aneurisma Aórtico/patologia , Implante de Prótese Vascular/efeitos adversos , Artéria Ilíaca/cirurgia , Remodelação Vascular , Idoso , Idoso de 80 Anos ou mais , Falso Aneurisma/diagnóstico por imagem , Falso Aneurisma/epidemiologia , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/patologia , Aneurisma Aórtico/diagnóstico por imagem , Aneurisma Aórtico/epidemiologia , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/epidemiologia , Aneurisma da Aorta Abdominal/patologia , Brasil/epidemiologia , Dilatação Patológica , Feminino , Humanos , Artéria Ilíaca/diagnóstico por imagem , Artéria Ilíaca/patologia , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
16.
J Vasc Res ; 57(4): 236-244, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32434199

RESUMO

INTRODUCTION AND OBJECTIVE: Interleukin (IL)-32 is a pro-inflammatory cytokine not previously studied in relation to abdominal aortic aneurysm (AAA). The aim of this study was to elucidate the expression and localization of IL-32 in AAA. METHODS: Expression and localization of IL-32 in human aortic tissue was studied with immunohistochemical analysis and Western blot (AAA: n = 5; controls: n = 4). ELISA was used to measure IL-32 in human plasma samples (AAA: n = 140; controls: n = 37) and in media from cultured peripheral blood mononuclear cells (PBMCs) from 3 healthy donors. IL-32 mRNA in PBMCs, endothelial cells, aortic smooth muscle cells (SMCs), and aortic tissue samples of AAA (n = 16) and control aortas (n = 9) was measured with qPCR. RESULTS: IL-32 was predominantly expressed in SMCs and T-cell-rich areas. Highest mRNA expression was observed in the intima/media layer of the AAA. A weaker protein expression was detected in non-aneurysmal aortas. Expression of IL-32 was confirmed in isolated T cells, macrophages, endothelial cells, and SMCs, where expression was also inducible by cytokines such as interferon-γ. There was no difference in IL-32 expression in plasma between patients and controls. CONCLUSION: IL-32 signaling is altered locally in AAA and could potentially play an important role in aneurysm development. Further studies using animal models would be helpful to study its potential role in AAA disease.


Assuntos
Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/metabolismo , Interleucinas/metabolismo , Adulto , Idoso , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/patologia , Estudos de Casos e Controles , Células Cultivadas , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Humanos , Interleucinas/genética , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Transdução de Sinais , Linfócitos T/metabolismo , Linfócitos T/patologia , Regulação para Cima , Adulto Jovem
17.
Ann Vasc Surg ; 68: 344-350, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32439528

RESUMO

BACKGROUND: Macrophages in the aneurysmal wall play an important role in the pathogenesis of abdominal aortic aneurysms (AAAs). Superparamagnetic iron oxide (SPIO) is a macrophage-specific contrast agent that results in negative enhancement on magnetic resonance imaging (MRI). SPIO-enhanced MRI targeting the intraluminal thrombus of AAAs has been previously reported. However, macrophages in the media and adventitia of AAA wall have not been investigated in detail. This study aimed to evaluate macrophage localization using SPIO-enhanced MRI in the media and adventitia of AAA wall, as macrophages play a crucial role in AAA pathogenesis. METHODS: Here, we included study and control patients planning to undergo open surgery for AAA. The study patients received SPIO injection 2 days preoperatively (the SPIO group, n = 7), whereas the control patients did not receive this injection (the control group). Ex vivo MRI was performed on the harvested AAA wall in the SPIO group during the surgery. The concordance between the number of macrophages and berlin blue (BB)-stained areas was histologically evaluated in both groups. Moreover, the concordance between regions of interest in MR images and BB-stained areas was evaluated. RESULTS: The proportion of BB-stained macrophages was higher in the SPIO group (0.93; interquartile range [IQR], 0.83-0.95) than in the control group (0.03; IQR, 0.026-0.11) (P < 0.05), indicating uptake of SPIO by macrophages in the AAA wall. A significant positive correlation was found between the number of BB-stained macrophages and BB-stained areas using Kendall rank correlation coefficient in the SPIO group (τ = 0.58; P < 0.05). Significant correlations were found in the distributions of the region of interest of SPIO-enhanced MRI and BB-stained areas in the media and adventitia in 5 of 7 patients. CONCLUSIONS: Macrophages present in the media and adventitia of the AAA wall showed an uptake of the SPIO contrast agent injected 2 days prior, which were then detected by ex vivo MRI. This suggests that SPIO-enhanced MR images help detect the localization of macrophages on the AAA wall, indicating its potential to serve as a novel index for AAA pathogenesis.


Assuntos
Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Meios de Contraste/administração & dosagem , Compostos Férricos/administração & dosagem , Macrófagos/patologia , Imagem por Ressonância Magnética , Idoso , Aorta Abdominal/patologia , Aorta Abdominal/cirurgia , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/cirurgia , Estudos de Casos e Controles , Corantes , Ferrocianetos , Humanos , Injeções , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Coloração e Rotulagem
18.
Eur J Vasc Endovasc Surg ; 60(2): 254-263, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32423743

RESUMO

OBJECTIVE: The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signalling pathway plays a pivotal role in abdominal aortic aneurysm (AAA). However, systemic inhibition of this pathway causes serious side effects, thus limiting the clinical use of pan-PI3K inhibitors. In this study, it was hypothesised that the γ subunit of PI3K plays an important role in the PI3K/AKT signalling pathway during AAA, and that specifically targeting PI3Kγ may prevent this process. METHODS: Aortic specimens were collected from AAA patients and organ donors. Furthermore, a classical AAA model in male C57BL/6 mice was created via an intra-aortic porcine pancreatic elastase (PPE) infusion and aortas were collected. A specific PI3Kγ inhibitor, IPI-549, was administered to mice orally. The protein expression level of PI3Kγ was examined by immunohistochemistry and western blotting. The aortic leukocytes were examined by immunohistochemistry and flow cytometry. RESULTS: PI3Kγ protein levels were elevated in the aortas of AAA patients and PPE infused mice. Three color immunofluorescence staining revealed the predominant area of PI3Kγ by T cells and macrophages in aneurysmal aortas. IPI-549 treatment significantly prevented AAA formation in mice. Aortic macrophages, T cells and neo-angiogenesis were significantly reduced in mice treated with IPI-549 compared with vehicle treated PPE infused mice. Flow cytometry analysis also revealed that CD45+ leukocytes and CD45+ F4/80+ macrophages in IPI-549 treated mouse aortas decreased dramatically. Additionally, IPI-549 treatment inhibited the phosphorylation of AKT in experimental aneurysmal lesions. CONCLUSION: Specific inhibition of PI3Kγ limits AAA formation. Targeting PI3Kγ prevents inflammatory cell infiltration through inhibition of AKT phosphorylation in AAA.


Assuntos
Aorta Abdominal/efeitos dos fármacos , Aneurisma da Aorta Abdominal/prevenção & controle , Classe Ib de Fosfatidilinositol 3-Quinase/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Idoso , Animais , Aorta Abdominal/enzimologia , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/enzimologia , Aneurisma da Aorta Abdominal/patologia , Estudos de Casos e Controles , Modelos Animais de Doenças , Feminino , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/enzimologia
19.
JAMA ; 323(20): 2029-2038, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32453369

RESUMO

Importance: Abdominal aortic aneurysms affect more than 3% of US older adults. Objective: To test whether doxycycline reduces the growth of abdominal aortic aneurysm over 2 years as measured by maximum transverse diameter. Design, Setting, and Participants: Parallel, 2-group, randomized clinical trial that was conducted at 22 US clinical centers between May 2013 and January 2017, and enrolled patients 50 years or older with small (3.5-5.0 cm for men, 3.5-4.5 cm for women) infrarenal aneurysms. The final date of follow-up was July 31, 2018. Interventions: Patients were randomized to receive twice daily for 2 years doxycycline 100 mg orally (as capsules) (n = 133) or placebo (n = 128). Main Outcomes and Measures: The primary outcome was change in abdominal aortic aneurysm maximum transverse diameter measured from CT images at baseline and follow-up at 2 years. Patients were assigned ranks based on the maximum transverse diameter (measured or imputed) of the aorta and also if they underwent aneurysm repair or died. The ranks were converted to scores having a normal distribution to facilitate the primary analysis ("normal scores"). Results: Of 261 patients randomized, no follow-up CT scans were obtained on 7 (3%), leaving a final analysis set of 129 patients assigned to doxycycline and 125 to placebo (mean [SD] age, 71.0 years [7.4 years], 35 women [14%]). The outcome normal scores used in the primary analysis were based on maximum transverse diameter (measured or imputed) in 113 patients (88%) in the doxycycline group and 112 patients (90%) in the placebo group; aneurysm repair in 13 (10%) and 9 (7%), and death in 3 (2%) and 4 (3%), respectively. The primary outcome, normal scores reflecting change in aortic diameter, did not differ significantly between the 2 groups, mean change in normal scores, 0.0262 vs -0.0258 (1-sided P = .71). Mean (SD) baseline maximum transverse diameter was 4.3 cm (0.4 cm) for doxycycline and 4.3 cm (0.4 cm) for placebo. At the 2-year follow-up, the change in measured maximum transverse diameter was 0.36 cm (95% CI, 0.31 to 0.40 cm) for 96 patients in the doxycycline group vs 0.36 cm (95% CI, 0.30 to 0.41 cm) for 101 patients in the placebo group (difference, 0.0; 95% CI, -0.07 to 0.07 cm; 2-sided P = .93). No patients were withdrawn from the study because of adverse effects. Joint pain occurred in 84 of 129 patients (65%) with doxycycline and 79 of 125 (63%) with placebo. Conclusions and Relevance: Among patients with small infrarenal abdominal aortic aneurysms, doxycycline compared with placebo did not significantly reduce aneurysm growth at 2 years. These findings do not support the use of doxycycline for reducing the growth of small abdominal aortic aneurysms. Trial Registration: ClinicalTrials.gov Identifier: NCT01756833.


Assuntos
Antibacterianos/uso terapêutico , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/tratamento farmacológico , Doxiciclina/uso terapêutico , Administração Oral , Idoso , Antibacterianos/efeitos adversos , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/crescimento & desenvolvimento , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/patologia , Doxiciclina/efeitos adversos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão/efeitos dos fármacos , Tomografia Computadorizada por Raios X , Falha de Tratamento
20.
Arterioscler Thromb Vasc Biol ; 40(6): 1559-1573, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32321307

RESUMO

OBJECTIVE: Excessive prostaglandin E2 production is a hallmark of abdominal aortic aneurysm (AAA). Enhanced expression of prostaglandin E2 receptor EP4 (prostaglandin E receptor 4) in vascular smooth muscle cells (VSMCs) has been demonstrated in human AAAs. Although moderate expression of EP4 contributes to vascular homeostasis, the roles of excessive EP4 in vascular pathology remain uncertain. We aimed to investigate whether EP4 overexpression in VSMCs exacerbates AAAs. Approach and Results: We constructed mice with EP4 overexpressed selectively in VSMCs under an SM22α promoter (EP4-Tg). Most EP4-Tg mice died within 2 weeks of Ang II (angiotensin II) infusion due to AAA, while nontransgenic mice given Ang II displayed no overt phenotype. EP4-Tg developed much larger AAAs than nontransgenic mice after periaortic CaCl2 application. In contrast, EP4fl/+;SM22-Cre;ApoE-/- and EP4fl/+;SM22-Cre mice, which are EP4 heterozygous knockout in VSMCs, rarely exhibited AAA after Ang II or CaCl2 treatment, respectively. In Ang II-infused EP4-Tg aorta, Ly6Chi inflammatory monocyte/macrophage infiltration and MMP-9 (matrix metalloprotease-9) activation were enhanced. An unbiased analysis revealed that EP4 stimulation positively regulated the genes binding cytokine receptors in VSMCs, in which IL (interleukin)-6 was the most strongly upregulated. In VSMCs of EP4-Tg and human AAAs, EP4 stimulation caused marked IL-6 production via TAK1 (transforming growth factor-ß-activated kinase 1), NF-κB (nuclear factor-kappa B), JNK (c-Jun N-terminal kinase), and p38. Inhibition of IL-6 prevented Ang II-induced AAA formation in EP4-Tg. In addition, EP4 stimulation decreased elastin/collagen cross-linking protein LOX (lysyl oxidase) in both human and mouse VSMCs. CONCLUSIONS: Dysregulated EP4 overexpression in VSMCs promotes inflammatory monocyte/macrophage infiltration and attenuates elastin/collagen fiber formation, leading to AAA exacerbation.


Assuntos
Aneurisma da Aorta Abdominal/etiologia , Inflamação/etiologia , Músculo Liso Vascular/metabolismo , Receptores de Prostaglandina E Subtipo EP4/fisiologia , Transdução de Sinais/fisiologia , Angiotensina II/administração & dosagem , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Aneurisma da Aorta Abdominal/patologia , Cloreto de Cálcio/administração & dosagem , Expressão Gênica , Regulação da Expressão Gênica/fisiologia , Humanos , Interleucina-6/genética , Macrófagos/patologia , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Knockout para ApoE , Camundongos Transgênicos , Monócitos/patologia , Músculo Liso Vascular/química , Miócitos de Músculo Liso/metabolismo , Proteína-Lisina 6-Oxidase/análise , Proteína-Lisina 6-Oxidase/genética , Receptores de Citocinas/genética , Receptores de Prostaglandina E Subtipo EP4/genética
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