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1.
Eur J Pharmacol ; 860: 172559, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31325435

RESUMO

Abdominal aortic aneurysm (AAA) is characterized with progressive weakening and considerable dilation of the aortic wall. Despite the high risk of mortality in the elderly population, there are still no clinical pharmacological therapies to alleviate AAA progression. Macrophage-derived MMP9 acts as a key factor in extracellular matrix degradation and is crucial for aortic aneurysm development and aortic rupture. Here, we demonstrated that the transcription level of MMP9 was suppressed with a concentration-dependent manner in macrophages after Imatinib treatment, which was accompanied by the down-regulation of MMP9 protein expression and reduced MMP9 secretion in vitro. Imatinib administration (50 mg/kg/d, i.g.) was carried out one week after the establishment of elastase-induced AAA in rats, stabilizing aneurysm progression and improving survival rate via decreasing the aortic diameter and preventing elastin degradation. Expression and activity of MMP9 in the artery tissues were significantly suppressed after Imatinib treatment via in situ assessment like immunohistochemistry and zymography, although macrophage infiltration was not affected. Furthermore, we found that Imatinib inhibited MMP9 transcription through reduction of STAT3 phosphorylation and translocation from nucleus to cytoplasm. These observations indicated that Imatinib prevents aneurysm progression by inhibiting STAT3-mediated MMP9 expression and activation, suggesting a new application of Imatinib on AAA clinical therapy.


Assuntos
Aneurisma da Aorta Abdominal/enzimologia , Aneurisma da Aorta Abdominal/prevenção & controle , Progressão da Doença , Mesilato de Imatinib/farmacologia , Macrófagos/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Elastase Pancreática/efeitos adversos , Animais , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/genética , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Macrófagos/enzimologia , Masculino , Metaloproteinase 9 da Matriz/genética , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/metabolismo
2.
J Vasc Res ; 56(5): 230-240, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31307051

RESUMO

OBJECTIVE: The relationship between methionine (Met) and abdominal aortic aneurysm (AAA) has been previously demonstrated, but the mechanisms controlling this association remain unclear. This study investigated the potential contribution of hypermethioninemia (HMet) to the development of AAA. METHODS: A model of AAA was induced by intraluminal porcine pancreatic elastase (PPE) infusion in 60 male Sprague-Dawley rats divided into 4 groups (n = 15 per group). Met was supplied by intragastric administration (1 g/kg body weight/day) from 1 week before surgery until 4 weeks after surgery. The aortic diameter was measured by ultrasound. Aortas were collected 4 weeks after surgery and subjected to biochemical analysis, histological assays, and transmission electron microscopy. RESULTS: After 5 weeks of Met supplementation, HMet increased the dilation ratio of the HMet + PPE group, and hyperhomocysteinemia was also induced in HMet and HMet + PPE rats. Increased matrix metalloproteinase-2 (MMP-2), osteopontin, and interleukin-6 expression was detected in HMet + PPE rats. Furthermore, increased autophagy was detected in the HMet + PPE group. CONCLUSION: This study demonstrates that HMet may exacerbate the formation of AAA due to the increased dilation ratio partially via enhancing MMP-2 and inflammatory responses.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/induzido quimicamente , Aneurisma da Aorta Abdominal/induzido quimicamente , Glicina N-Metiltransferase/deficiência , Metionina , Erros Inatos do Metabolismo dos Aminoácidos/sangue , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/ultraestrutura , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Dilatação Patológica , Modelos Animais de Doenças , Progressão da Doença , Glicina N-Metiltransferase/sangue , Interleucina-6/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Osteopontina/metabolismo , Elastase Pancreática , Ratos Sprague-Dawley , Fatores de Risco , Fatores de Tempo
3.
Eur J Pharmacol ; 856: 172403, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31128093

RESUMO

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.


Assuntos
Angiotensina II/farmacologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/prevenção & controle , Apolipoproteínas E/deficiência , Ácido Benzoico/farmacologia , Quimases/antagonistas & inibidores , Inibidores de Serino Proteinase/farmacologia , Animais , Aneurisma da Aorta Abdominal/metabolismo , Colite/prevenção & controle , Precursores Enzimáticos/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C
4.
Circ Cardiovasc Imaging ; 12(3): e008707, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30871334

RESUMO

BACKGROUND: Molecular magnetic resonance imaging is a promising modality for the characterization of abdominal aortic aneurysms (AAAs). The combination of different molecular imaging biomarkers may improve the assessment of the risk of rupture. This study investigates the feasibility of imaging inflammatory activity and extracellular matrix degradation by concurrent dual-probe molecular magnetic resonance imaging in an AAA mouse model. METHODS: Osmotic minipumps with a continuous infusion of Ang II (angiotensin II; 1000 ng/[kg·min]) to induce AAAs were implanted in apolipoprotein-deficient mice (N=58). Animals were assigned to 2 groups. In group 1 (longitudinal group, n=13), imaging was performed once after 1 week with a clinical dose of a macrophage-specific iron oxide-based probe (ferumoxytol, 4 mgFe/kg, surrogate marker for inflammatory activity) and an elastin-specific gadolinium-based probe (0.2 mmol/kg, surrogate marker for extracellular matrix degradation). Animals were then monitored with death as end point. In group 2 (week-by-week-group), imaging with both probes was performed after 1, 2, 3, and 4 weeks (n=9 per group). Both probes were evaluated in 1 magnetic resonance session. RESULTS: The combined assessment of inflammatory activity and extracellular matrix degradation was the strongest predictor of AAA rupture (sensitivity 100%; specificity 89%; area under the curve, 0.99). Information from each single probe alone resulted in lower predictive accuracy. In vivo measurements for the elastin- and iron oxide-probe were in good agreement with ex vivo histopathology (Prussian blue-stain: R2=0.96, P<0.001; Elastica van Giesson stain: R2=0.79, P<0.001). Contrast-to-noise ratio measurements for the iron oxide and elastin-probe were in good agreement with inductively coupled mass spectroscopy ( R2=0.88, R2=0.75, P<0.001) and laser ablation coupled to inductively coupled plasma-mass spectrometry. CONCLUSIONS: This study demonstrates the potential of the concurrent assessment of inflammatory activity and extracellular matrix degradation by dual-probe molecular magnetic resonance imaging in an AAA mouse model. Based on the combined information from both molecular probes, the rupture of AAAs could reliably be predicted.


Assuntos
Aorta Abdominal/diagnóstico por imagem , Meios de Contraste/administração & dosagem , Elastina/metabolismo , Matriz Extracelular/metabolismo , Óxido Ferroso-Férrico/administração & dosagem , Gadolínio DTPA/administração & dosagem , Mediadores da Inflamação/metabolismo , Imagem por Ressonância Magnética , Imagem Molecular/métodos , Angiotensina II , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Ruptura Aórtica/induzido quimicamente , Ruptura Aórtica/diagnóstico por imagem , Ruptura Aórtica/metabolismo , Ruptura Aórtica/patologia , Modelos Animais de Doenças , Progressão da Doença , Matriz Extracelular/patologia , Estudos de Viabilidade , Gadolínio DTPA/análogos & derivados , Masculino , Camundongos Knockout para ApoE , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Fatores de Tempo
5.
J Vasc Surg ; 70(2): 588-598.e2, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30792060

RESUMO

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


Assuntos
Anticorpos Neutralizantes , Aorta Abdominal/enzimologia , Aneurisma da Aorta Abdominal/enzimologia , Arginase/metabolismo , Macrófagos/enzimologia , Elastase Pancreática , Fator de Crescimento Transformador beta/metabolismo , Animais , Aorta Abdominal/imunologia , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/imunologia , Aneurisma da Aorta Abdominal/patologia , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/metabolismo , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Fenótipo , Transdução de Sinais , Fator de Crescimento Transformador beta/imunologia , Regulação para Cima
6.
Hypertension ; 73(3): 547-560, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30686087

RESUMO

p53-dependent vascular smooth muscle cell senescence is a key pathological process of abdominal aortic aneurysm (AAA). Caloric restriction (CR) is a nonpharmacological intervention that prevents AAA formation. However, whether p53 is indispensable to the protective role of CR remains unknown. In this study, we investigated the necessity of p53 in the beneficial role of CR in AAA formation and the underlying mechanisms. We subjected p53+/+ and p53-/- mice to 12 weeks of CR and then examined the incidence of Ang II (angiotensin II)-induced AAA formation. We found that both CR and p53 knockout reduced Ang II-induced AAA formation; however, CR markedly increased the incidence of AAA formation and exacerbated aortic elastin degradation in p53-/- mice, accompanied by increased vascular senescence, reactive oxygen species generation, and reduced energy production. Analysis of mitochondrial respiratory activity revealed that dysfunctional complex IV accounts for the abnormal mitochondrial respiration in p53-/- vascular smooth muscle cells treated by CR serum. Mechanistically, ablation of p53 almost totally blocked the protective role of CR by inhibiting SCO2 (cytochrome C oxidase assembly protein 2)-dependent mitochondrial complex IV activity. Overexpression of SCO2 restored the beneficial effect of CR on antagonizing Ang II-induced expression of AAA-related molecules and reactive oxygen species generation in p53-/- vascular smooth muscle cells. Together, our findings demonstrate that the existence of p53 in vascular smooth muscle cells is critical to the protective role of CR in Ang II-induced AAA formation by maintaining an appropriate mitochondrial function.


Assuntos
Aneurisma da Aorta Abdominal/terapia , Restrição Calórica/métodos , Metabolismo Energético/fisiologia , Músculo Liso Vascular/metabolismo , Proteína Supressora de Tumor p53/genética , Angiotensina II/toxicidade , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/genética , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo
7.
J Oleo Sci ; 68(1): 79-85, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30606956

RESUMO

Abdominal aortic aneurysm (AAA) is a vascular disease characterized by the weakening of the vascular walls and the progressive dilation of the abdominal aorta. Nicotine, a primary component of cigarette smoke, is associated with AAA development and rupture. Nicotine induces AAA development by weakening vascular walls. However, little is known about preventive methods using functional food factors for nicotine-induced vascular destruction. Sesamin and sesamolin are functional food factors that are fat-soluble lignans found in Sesamum indicum seeds. Previous reports indicated that sesamin and sesamolin have anti-oxidative and anti-inflammatory effects. In this study, we evaluated the effects of sesamin and sesamolin-rich sesame extract on the weakening of vascular walls in nicotine-administered mice. Sesame extract attenuated the degradation of collagen and elastin fibers caused by nicotine. In addition, sesame extract decreased the area positive for matrix metalloproteinase 12 (MMP-12) and oxidative stress in the vascular walls. These results suggest that sesame extract may decrease the weakening of vascular walls by suppressing the nicotine-induced degradation of collagen and elastin fibers. Sesame extract may be effective in preventing AAA development by decreasing both, MMP-12 expression and oxidative stress in vascular walls.


Assuntos
Aorta Torácica/efeitos dos fármacos , Aneurisma da Aorta Abdominal/prevenção & controle , Colágeno/metabolismo , Elastina/metabolismo , Extratos Vegetais/uso terapêutico , Animais , Aneurisma da Aorta Abdominal/induzido quimicamente , Peso Corporal/efeitos dos fármacos , Dioxóis/uso terapêutico , Ingestão de Alimentos/efeitos dos fármacos , Lignanas/uso terapêutico , Masculino , Metaloproteinase 12 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Nicotina , Estresse Oxidativo/efeitos dos fármacos , Sesamum/química
8.
Arterioscler Thromb Vasc Biol ; 39(3): 446-458, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30651000

RESUMO

Objective- Inflammation occurs during the progression of abdominal aortic aneurysm (AAA). IL (interleukin)-33 is a pleiotropic cytokine with multiple immunomodulatory effects, yet its role in AAA remains unknown. Approach and Results- Immunoblot, immunohistochemistry, and immunofluorescent staining revealed increased IL-33 expression in adventitia fibroblasts from mouse AAA lesions. Daily intraperitoneal administration of recombinant IL-33 or transgenic IL-33 expression ameliorated periaorta CaPO4 injury- and aortic elastase exposure-induced AAA in mice, as demonstrated by blunted aortic expansion, reduced aortic wall elastica fragmentation, enhanced AAA lesion collagen deposition, attenuated T-cell and macrophage infiltration, reduced inflammatory cytokine production, skewed M2 macrophage polarization, and reduced lesion MMP (matrix metalloproteinase) expression and cell apoptosis. Flow cytometry analysis, immunostaining, and immunoblot analysis showed that exogenous IL-33 increased CD4+Foxp3+ regulatory T cells in spleens, blood, and aortas in periaorta CaPO4-treated mice. Yet, ST2 deficiency muted these IL-33 activities. Regulatory T cells from IL-33-treated mice also showed significantly stronger activities in suppressing smooth muscle cell inflammatory cytokine and chemokine expression, macrophage MMP expression, and in increasing M2 macrophage polarization than those from vehicle-treated mice. In contrast, IL-33 failed to prevent AAA and lost its beneficial activities in CaPO4-treated mice after selective depletion of regulatory T cells. Conclusions- Together, this study established a role of IL-33 in protecting mice from AAA formation by enhancing ST2-dependent aortic and systemic regulatory T-cell expansion and their immunosuppressive activities.


Assuntos
Aneurisma da Aorta Abdominal/prevenção & controle , Interleucina-33/fisiologia , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Aorta/imunologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/imunologia , Fosfatos de Cálcio/toxicidade , Células Cultivadas , Citocinas/biossíntese , Avaliação Pré-Clínica de Medicamentos , Injeções Intraperitoneais , Proteína 1 Semelhante a Receptor de Interleucina-1/deficiência , Proteína 1 Semelhante a Receptor de Interleucina-1/fisiologia , Interleucina-33/genética , Interleucina-33/farmacologia , Interleucina-33/uso terapêutico , Macrófagos/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Elastase Pancreática/toxicidade , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Linfócitos T Reguladores/imunologia , Remodelação Vascular
9.
Vasc Endovascular Surg ; 53(1): 35-41, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30373483

RESUMO

OBJECTIVE:: This study aimed to observe the effect of pancreatic elastase combined with angiotensin II on a stable rabbit abdominal aortic aneurysm model. METHODS:: A total of 20 male New Zealand rabbits were randomly divided into groups A and B, with 10 rabbits per group. The rabbits in group A were given an intraperitoneal perfusion of pancreatic elastase, and the rabbits in group B were given continuous pumping of angiotensin II in addition to the operation of group A. Before the operation and at 2, 4, and 16 weeks postoperation, vascular color Doppler ultrasonography was performed, and blood samples were collected to measure the serum matrix metalloproteinase 9 (MMP9) and MMP2 levels. At 16 weeks postoperation, all rabbits in both groups were killed, and hematoxylin and eosin, Elastic-van-Gieson, Masson's, and immunohistochemical staining were performed for the vessel specimens. RESULTS:: At 2 weeks postoperation, the aneurysm formation rates of the 2 groups were both 100%, and the average expansion rates of the aneurysm diameters were 85% and 93%, respectively; these differences were not significant ( P = .150 and P = .280, respectively). At 4 weeks postoperation, the aneurysm formation rates of the 2 groups were 71.4% and 100%, and the average expansion rates of the aneurysm diameter were 68% and 99%, respectively; the differences between the groups were significant ( P = .031 and P = .022, respectively). At 16 weeks postoperation, the aneurysm formation rates of the 2 groups were 14.3% and 100%, and the average expansion rates of the aneurysm diameter were 12% and 108%, respectively; the differences between the groups were significant ( P = .026 and P = .014, respectively). CONCLUSION:: Compared to the abdominal aortic aneurysm modeling method in rabbits based on pancreatic elastase alone, the abdominal aortic aneurysm modeling method in rabbits using pancreatic elastase combined with angiotensin II maintained the morphology of the abdominal aortic aneurysm for a longer time, showing an important application value for the long-term observation of changes in abdominal aortic aneurysms.


Assuntos
Angiotensina II , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Elastase Pancreática , Remodelação Vascular , Animais , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/enzimologia , Aorta Abdominal/fisiopatologia , Aneurisma da Aorta Abdominal/enzimologia , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/fisiopatologia , Dilatação Patológica , Modelos Animais de Doenças , Progressão da Doença , Hemodinâmica , Masculino , Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Coelhos , Fatores de Tempo , Ultrassonografia Doppler em Cores
10.
Heart Vessels ; 34(5): 875-882, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30535755

RESUMO

Inflammation plays a critical role in the development of abdominal aortic aneurysm (AAA). Chemokine receptor CXCR2 mediates inflammatory cell chemotaxis in several diseases. However, the role of CXCR2 in AAA and the underlying mechanisms remain unknown. In this study, we found that the CXCR2 expressions in AAA tissues from human and angiotensin II (Ang II)-infused apolipoprotein E knockout (Apo E-/-) mice were significantly increased. The pharmacological inhibition of CXCR2 (SB265610) markedly reduced Ang II-induced AAA formation. Furthermore, SB265610 treatment significantly reduced collagen deposition, elastin degradation, the metal matrix metalloprotease expression and accumulation of macrophage cells. In conclusion, these results showed CXCR2 plays a pathogenic role in AAA formation. Inhibition of CXCR2 pathway may represent a novel therapeutic approach to treat AAA.


Assuntos
Aneurisma da Aorta Abdominal/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Receptores de Interleucina-8B/antagonistas & inibidores , Triazóis/farmacologia , Angiotensina II/efeitos adversos , Animais , Aneurisma da Aorta Abdominal/induzido quimicamente , Modelos Animais de Doenças , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Knockout para ApoE , Transdução de Sinais
11.
J Vasc Surg ; 70(1): 252-260.e2, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30591288

RESUMO

OBJECTIVE: Few large-animal models exist for the study of aortic aneurysms. ß-Aminopropionitrile (BAPN) is a compound known to cause aortic aneurysms by inhibiting lysyl oxidase, a collagen cross-linking enzyme. It is hypothesized that BAPN plus aneurysm induction surgery would result in significant aneurysm formation in swine with biologic properties similar to human disease. METHODS: Initial experiments were performed in uncastrated male swine not treated with BAPN (surgery alone). Subsequently, uncastrated male swine were fed BAPN (0.15 g/kg) for 7 days before undergoing surgery; the infrarenal aorta was circumferentially dissected and measured, balloon dilated, and perfused with elastase (500 units) and type I collagenase (8000 units), with extraluminal elastase application. In the BAPN groups, daily BAPN feedings continued until swine harvest at postoperative days 7, 14, and 28. RESULTS: Swine undergoing surgery alone (n = 12) had significantly less dilation at 28 days compared with BAPN + surgery swine (51.9% ± 29.2% [0%-100%] vs 113.5% ± 30.2% [52.9%-146.2%]; P < .0003). Mean aortic dilation in animals undergoing treatment with surgery and BAPN was 86.9% ± 47.4% (range, 55.6%-157.1%), 105.4% ± 58.1% (50%-133.3%), and 113.5% ± 30.2% (52.9%-146.2%) at 7, 14, and 28 days, respectively. In the BAPN + surgery group, significant elastolysis was present at all time points, whereas aortic wall collagen content was not significantly different. Smooth muscle cells were significantly depleted at 14 and 28 days, and M1 macrophages were increased at 14 and 28 days (P < .05, all). Matrix metalloproteinase 2 was elevated at 7 days (P < .05). Multiple proinflammatory cytokines were elevated within the aortic wall of BAPN + surgery swine. CONCLUSIONS: BAPN plus surgery resulted in significantly larger aortic aneurysms than surgery alone and was critical to aneurysm formation in this novel swine model. Hallmarks of human disease, such as elastin fragmentation, smooth muscle cell depletion, macrophage infiltration, matrix metalloproteinase activation, and proinflammatory cytokine expression, were observed in BAPN-treated swine. This model better parallels many of the characteristics of human AAAs and may be suitable for prehuman drug trials.


Assuntos
Aminopropionitrilo , Angioplastia com Balão , Aorta Abdominal , Aneurisma da Aorta Abdominal/induzido quimicamente , Colagenases , Elastase Pancreática , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Citocinas/metabolismo , Dilatação Patológica , Modelos Animais de Doenças , Progressão da Doença , Mediadores da Inflamação/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Sus scrofa , Fatores de Tempo , Remodelação Vascular
12.
Arterioscler Thromb Vasc Biol ; 39(2): 212-223, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30580570

RESUMO

Objective- Abdominal aortic aneurysm is caused by the accumulation of inflammatory cells in the aortic wall. Our recent studies demonstrated that inhibition of Notch signaling attenuates abdominal aortic aneurysm formation by shifting the macrophage balance towards anti-inflammatory (M2) phenotype. Using IL12p40-/- (interleukin 12 p40) mice, we investigated the effects of M2-predominant macrophages on the development of abdominal aortic aneurysm. Approach and Results- Male (8-10 week-old) wild-type and IL12p40-/- mice (n=15) on C57BL/6 background were infused with Ang II (angiotensin II, 1000 ng/kg per minute) by implanting osmotic pumps subcutaneously for 28 days. In the IL12p40-/- mice, Ang II significantly increased the maximal intraluminal diameter (9/15) as determined by transabdominal ultrasound imaging. In addition, IL12p40-deletion significantly increased aortic stiffness in response to Ang II as measured by pulse wave velocity and atomic force microscopy. Histologically, IL12p40-/- mice exhibited increased maximal external diameter of aorta and aortic lesions associated with collagen deposition and increased elastin fragmentation compared with wild-type mice infused with Ang II. Mechanistically, IL12p40 deficiency by siRNA (small interfering RNA) augmented the Tgfß2-mediated Mmp2 expression in wild-type bone marrow-derived macrophages without affecting the expression of Mmp9. No such effects of IL12p40 deficiency on MMP2/MMP9 was observed in human aortic smooth muscle cells or fibroblasts. Depletion of macrophages in IL12p40-/- mice by clodronate liposomes significantly decreased the maximal external diameter of aorta and aortic stiffness in response to Ang II as determined by imaging and atomic force microscopy. Conclusions- IL12p40 depletion promotes the development of abdominal aortic aneurysm, in part, by facilitating recruitment of M2-like macrophages and potentiating aortic stiffness and fibrosis mediated by Tgfß2.


Assuntos
Angiotensina II/farmacologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Subunidade p40 da Interleucina-12/fisiologia , Animais , Colágeno/metabolismo , Subunidade p40 da Interleucina-12/deficiência , Macrófagos/fisiologia , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fator de Crescimento Transformador beta2/fisiologia , Rigidez Vascular
13.
Acta Pharmacol Sin ; 40(2): 192-198, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29777203

RESUMO

Abdominal aortic aneurysms (AAAs) are a chronic vascular disease characterized by pathological luminal dilation. Aortic rupture is the fatal consequence of AAAs. Ginkgo biloba extracts (GBEs), a natural herb extract widely used as food supplements, drugs, and cosmetics, has been reported to suppress development of calcium chloride-induced AAAs in mice. Calcium chloride-induced AAAs do not rupture, while angiotensin II (AngII)-induced AAAs in mice have high rate of aortic rupture, implicating potentially different mechanisms from calcium chloride-induced AAAs. This study aimed to determine whether GBE would improve aortic dilation and rupture rate of AngII-induced AAAs. Male apolipoprotein E (apoE) -/- mice were infused with AngII and administered either GBE or its major active ingredients, flavonoids and ginkgolides, individually or in combination. To determine the effects of GBE in mice with established AAAs, male apoE-/- mice were firstly infused with AngII for 28 days to develop AAAs, and then administered either GBE or vehicle in mice with established AAAs, which were continuously infused with AngII for another 56 days. GBE, but not the two major active components separately or synergistically, prevented aortic rupture, but not aortic dilation. The protection of GBE from aortic rupture was independent of systolic blood pressure, lipid, and inflammation. GBE also did not attenuate either aortic rupture or progressive aortic dilation in mice with established AAAs. GBE did not reduce the atherosclerotic lesion areas, either. In conclusion, GBE prevents aortic rupture in AngII-infused hypercholesterolemic mice, but only in the early phase of the disease development.


Assuntos
Aneurisma da Aorta Abdominal/prevenção & controle , Ruptura Aórtica/prevenção & controle , Ginkgo biloba/química , Extratos Vegetais/uso terapêutico , Angiotensina II , Animais , Aneurisma da Aorta Abdominal/induzido quimicamente , Ruptura Aórtica/induzido quimicamente , Apolipoproteínas E/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout
14.
Mol Med Rep ; 19(2): 1396-1402, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30535428

RESUMO

Gamboge is the dry resin secreted by Garcinia hanbaryi Hook.f, with the function of promoting blood circulation and anti­cancer effects, detoxification, hemostasis and killing insects. It is also used for the treatment of cancer, brain edema and other diseases. Gambogic acid is the main effective constituent of Gamboge. The present study tested the hypothesis that the effect of Gambogic acid prevents angiotensin II­induced abdominal aortic aneurysm (AAA), and explored its underlying mechanism. It was demonstrated that gambogic acid significantly inhibited AAA incidence rate, and reduced edge leading aortic diameter and aortic wall thickness in AAA mice. Gambogic acid treatment markedly decreased the levels of proinflammatory cytokines and oxidative stress factors, and transforming growth factor­ß (TGF­ß) and matrix metalloproteinase (MMP)­2 and MMP­9 protein expression in AAA mice. Furthermore, Gambogic acid decreased expression of phosphatidylinositol 3­kinase (PI3K), and phosphorylation of protein kinase B (Akt), mechanistic target of rapamycin (mTOR) and p70­S6 kinase 1. It also suppressed nuclear factor (NF)­κB protein expression in AAA mice. The findings of the present study indicated that Gambogic acid prevents angiotensin II­induced AAA through inflammatory and oxidative stress­dependent targeting of the PI3K/Akt/mTOR and NF­κB signaling pathways.


Assuntos
Angiotensina II/farmacologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/prevenção & controle , Inflamação/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Xantonas/farmacologia , Animais , Aneurisma da Aorta Abdominal/metabolismo , Garcinia/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo
15.
J Vasc Surg ; 68(6S): 93S-103S, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30470363

RESUMO

OBJECTIVE: Resolvins have been shown to attenuate inflammation, whereas NETosis, the process of neutrophils releasing neutrophil extracellular traps (NETs), produces increased inflammation. It is hypothesized that treatment of animals with resolvin D1 (RvD1) would reduce abdominal aortic aneurysm (AAA) formation by inhibiting NETosis. METHODS: Wild-type 8- to 12-week-old C57BL/6 male mice (n = 47) and apolipoprotein E-deficient (ApoE-/-) mice (n = 20) were used in two models to demonstrate the effects of RvD1 on AAA growth. In the topical elastase AAA model, wild-type mice were divided into three groups: a deactivated elastase control group, in which sham surgery was performed using deactivated elastase and mice were intravenously injected with phosphate-buffered saline (PBS) once a day until harvest; an elastase group, in which active elastase was used to induce AAA and mice were injected with PBS daily until harvest; and an RvD1-treated group, in which AAA was induced and mice were injected with RvD1 daily until harvest. In the angiotensin II (Ang II)-induced AAA model, ApoE-/- mice were fed a high-fat diet and implanted with osmotic infusion pumps containing Ang II (1000 ng/kg/min). The Ang II model was divided into two groups: an Ang II control group, in which Ang II was delivered and mice were injected with PBS daily until harvest; and an RvD1-treated group, in which Ang II was delivered and mice were injected with RvD1 daily until harvest. On postoperative day 3, day 14, or day 28, aortic and blood samples were collected for Western blot, histology, cytokine array, enzyme-linked immunosorbent assay, and gelatin zymography after aortic diameter measurement. RESULTS: The day 14 RvD1-treated group demonstrated 42% reduced AAA diameter compared with the elastase group (P < .001). On postoperative day 3, the RvD1-treated group showed decreased levels of NETosis markers citrullinated histone H3 (P = .04) and neutrophil elastase (P = .002) compared with the elastase group. Among important cytokines involved in AAA formation, interleukin (IL) 1ß was downregulated (P = .02) whereas IL-10, a protective cytokine, was upregulated (P = .01) in the RvD1-treated group. Active matrix metalloproteinase 2 also decreased in the RvD1-treated group (P = .03). The RvD1-treated group in the Ang II AAA model, a second model, demonstrated reduced AAA diameter compared with the Ang II control group on day 28 (P < .046). The RvD1-treated group showed decreased levels of citrullinated histone H3 on day 3 (P = .002). Cytokines interferon γ, IL-1ß, C-X-C motif chemokine ligand 10, monocyte chemotactic protein 1, and regulated on activation, normal T cell expressed and secreted (RANTES) were all decreased on day 28 (P < .05). CONCLUSIONS: RvD1-mediated inhibition of NETosis may represent a future medical treatment for the attenuation of AAA growth.


Assuntos
Anti-Inflamatórios/farmacologia , Aorta Abdominal/efeitos dos fármacos , Aneurisma da Aorta Abdominal/prevenção & controle , Ácidos Docosa-Hexaenoicos/farmacologia , Armadilhas Extracelulares/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Citrulinação , Citocinas/metabolismo , Modelos Animais de Doenças , Armadilhas Extracelulares/metabolismo , Histonas/metabolismo , Mediadores da Inflamação/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Neutrófilos/metabolismo , Neutrófilos/patologia , Elastase Pancreática , Remodelação Vascular/efeitos dos fármacos
16.
Sci Rep ; 8(1): 16645, 2018 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-30413751

RESUMO

Abdominal aortic aneurysm (AAA) refers to a localized dilation of the abdominal aorta that exceeds the normal diameter by 50%. AAA pathophysiology is characterized by progressive inflammation, vessel wall destabilization and thrombus formation. Our aim was to investigate the potential involvement of von Willebrand factor (VWF), a thrombo-inflammatory plasma protein, in AAA pathophysiology using a dissection-based and angiotensin II infusion-induced AAA mouse model. AAA formation was induced in both wild-type and VWF-deficient mice by subcutaneous implantation of an osmotic pump, continuously releasing 1000 ng/kg/min angiotensin II. Survival was monitored, but no significant difference was observed between both groups. After 28 days, the suprarenal aortic segment of the surviving mice was harvested. Both AAA incidence and severity were similar in wild-type and VWF-deficient mice, indicating that AAA formation was not significantly influenced by the absence of VWF. Although VWF plasma levels increased after the infusion period, these increases were not correlated with AAA progression. Also detailed histological analyses of important AAA hallmarks, including elastic degradation, intramural thrombus formation and leukocyte infiltration, did not reveal differences between both groups. These data suggest that, at least in the angiotensin II infusion-induced AAA mouse model, the role of VWF in AAA pathophysiology is limited.


Assuntos
Angiotensina II/toxicidade , Aneurisma da Aorta Abdominal/patologia , Dilatação Patológica/patologia , Modelos Animais de Doenças , Inflamação/patologia , Fator de von Willebrand/fisiologia , Animais , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/metabolismo , Dilatação Patológica/induzido quimicamente , Dilatação Patológica/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Vasoconstritores/toxicidade
17.
J Mol Cell Cardiol ; 125: 6-17, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30336142

RESUMO

Endothelial cell derived secretive factors play pivotal roles maintaining the homeostasis by influencing the behaviors of other cells. When dysregulated, these factors may contribute to the disruption of physiological integrity and promote disease genesis in a number of different tissues and organs. In the present study we investigated how targeted deletion of brahma related gene 1 (Brg1), a chromatin remodeling protein, in endothelium might affect the pathogenesis of abdominal aortic aneurysm (AAA) induced by calcium chloride (CaCl2). We report here that compared to the wild type (WT) littermates, endothelial conditional Brg1 knockout (ecKO) mice exhibited an attenuated phenotype of AAA. Immunostaining and quantitative PCR analyses showed that vascular inflammation was suppressed in ecKO mice as opposed to WT mice likely due to diminished recruitment of macrophages. Further examination revealed that Brg1 deficiency led to a reduction in colony stimulating factor 1 (CSF1) levels. In cultured endothelial cells, Brg1 cooperated with histone H3K9 demethylase KDM3A to activate CSF1 transcription and macrophage recruitment thereby perpetuating vascular inflammation. Depletion of BRG1 or KDM3A in endothelial cells dampened CSF1 production and attenuated macrophage chemotaxis. Therefore, our data suggest that epigenetic activation of CSF1 transcription by Brg1 may contribute to AAA pathogenesis.


Assuntos
Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/metabolismo , Cloreto de Cálcio/toxicidade , DNA Helicases/metabolismo , Endotélio/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Animais , Movimento Celular/efeitos dos fármacos , Imunoprecipitação da Cromatina , Fatores Estimuladores de Colônias , DNA Helicases/genética , Feminino , Fator Estimulador de Colônias de Macrófagos , Masculino , Camundongos , Camundongos Knockout , Proteínas Nucleares/genética , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Transcrição/genética
18.
Hypertension ; 72(5): 1189-1199, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30354818

RESUMO

Abdominal aortic aneurysm (AAA) is a common vascular degenerative disease. PARP-1 (poly[ADP-ribose] polymerase 1) is a nuclear enzyme, which plays a critical role in vascular diseases. We hypothesized that PARP-1 inhibition might have protective effects on AAA. In vivo, Ang II (angiotensin II) was continuously infused by a micropump for 28 days to induce AAA in mice. In vitro, aortic endothelial cells and smooth muscle cells were stimulated by Ang II for 24 hours. Ang II infusion increased PARP-1 expression and activity and successfully induced AAA formation partly with a hemorrhage in ApoE-/- mice. Genetic deletion of PARP-1 markedly reduced the AAA incidence, abdominal aortic diameter, macrophage infiltration, ICAM-1 (intercellular adhesion molecule 1) and VCAM-1 (vascular adhesion molecule 1) expression, and MMP (matrix metalloproteinase) expression, as well as MMP activity; but increased smooth muscle cells content and collagens expression in AAA. PARP-1 inhibition by PJ-34 also exerted a protective effect on AAA in mice. In aortic endothelial cells, Ang II-induced oxidative stress and DNA damage, resulting in increased PARP-1 expression and activity. Compared with the control, Ang II increased TNF-α (tumor necrosis factor α) and IL-6 (interleukin-6) secretions, ICAM-1 expression and THP-1 (human acute monocytic leukemia cell line) cells adhesion, while PARP-1 inhibition by siRNA reduced the inflammatory response probably through inhibition of the phosphorylation of ERK (extracellular signal-regulated kinase), NF-κB (nuclear factor-κB), and Akt signaling pathways. In smooth muscle cells, Ang II promoted cell migration, proliferation, and apoptosis, reduced collagens expression, but increased MMPs expression, while PARP-1 deletion alleviated these effects partly by reducing NF-κB-targeted MMP-9 expression. PARP-1 inhibition might be a feasible strategy for the treatment of AAA.


Assuntos
Aneurisma da Aorta Abdominal/prevenção & controle , Pressão Sanguínea/fisiologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Angiotensina II , Animais , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Colágeno/metabolismo , Citocinas/metabolismo , Dano ao DNA/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Camundongos , Camundongos Knockout , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Poli(ADP-Ribose) Polimerase-1/genética , RNA Interferente Pequeno , Transdução de Sinais/efeitos dos fármacos
19.
J Nutr Sci Vitaminol (Tokyo) ; 64(4): 271-276, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30175790

RESUMO

Abdominal aortic aneurysm (AAA) is a vascular disease characterized by chronic inflammation in the infrarenal aorta. Epidemiologic data have clearly linked tobacco smoking to aneurysm formation and a faster rate of expansion. It suggested that nicotine, one of the main ingredients of tobacco, has been suggested to be associated with AAA development and rupture. In the condition where no established drugs are available; therefore, an effective approach to prevent the vascular damage from nicotine consumption may be the use of dietary functional food factors. However, little is known about the relationship between dietary components and AAA. In this study, we estimated the effect of dietary deoxyribonucleic acid (DNA) on the vascular wall. After habituation for 5 d, the mice were divided into four groups: control diet and distilled water group (C), DNA-Na diet and distilled water group (DNA), control diet and 0.5 mg/mL nicotine solution group (C-Nic), DNA-Na diet, and 0.5 mg/mL nicotine solution group (DNA-Nic). The dietary DNA attenuated the degradation of elastin fibers induced by nicotine administration. The areas stained positive for MMP-2 in the DNA-Nic group were significantly suppressed compared to C-Nic mice. These data suggest that the dietary DNA may prevent the weakening of the aortic wall via inhibition of the MMP-2-dependent pathway. In conclusion, we have revealed the protective effect of dietary DNA on the vascular pathology of nicotine-administrated mice. A nucleic acid-rich diet might be useful for people who consume nicotine via smoking, chewing tobacco, or nicotine patches.


Assuntos
Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/prevenção & controle , DNA/uso terapêutico , Suplementos Nutricionais , Modelos Animais de Doenças , Elastina/metabolismo , Endotélio Vascular/metabolismo , Túnica Adventícia/efeitos dos fármacos , Túnica Adventícia/imunologia , Túnica Adventícia/metabolismo , Túnica Adventícia/patologia , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Antioxidantes/uso terapêutico , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/imunologia , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Fármacos Cardiovasculares/uso terapêutico , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Imuno-Histoquímica , Masculino , Metaloproteinase 2 da Matriz/química , Metaloproteinase 2 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Nicotina/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Proteólise/efeitos dos fármacos
20.
Surgery ; 164(5): 1087-1092, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30174141

RESUMO

BACKGROUND: Tamsulosin, an α1A-adrenergic receptor inhibitor, is prescribed to treat benign prostatic hyperplasia in men >60 years of age, the same demographic most susceptible to abdominal aortic aneurysm. The goal of this study was to investigate the effect of tamsulosin on abdominal aortic aneurysm pathogenesis. METHODS: Abdominal aortic aneurysms were induced in WT C57BL/6 male mice (n = 9-18/group), using an established topical elastase abdominal aortic aneurysm model. Osmotic pumps were implanted in mice 5 days before operation to create the model, administering either low dose (0.125 µg/day tamsulosin), high dose (0.250µg/day tamsulosin), or vehicle treatments with and without topical application of elastase. Blood pressures were measured preoperatively and on postoperative days 0, 3, 7, and 14. On postoperative day 14, aortic diameter was measured before harvest. Sample aortas were prepared for histology and cytokine analysis. RESULTS: Measurements of systolic blood pressure did not differ between groups. Mice treated with the low dose of tamsulosin and with the high dose of tamsulosin showed decreased aortic diameter compared with vehicle-treated control (93% ± 24 versus 94% ± 30 versus 132% ± 24, respectively; P = .0003, P = .0003). Cytokine analysis demonstrated downregulation of pro-inflammatory cytokines in both treatment groups compared with the control (P < .05). Histology exhibited preservation of elastin in both low- and high-dose tamsulosin-treated groups (P = .0041 and P = .0018, respectively). CONCLUSION: Tamsulosin attenuates abdominal aortic aneurysm formation with increased preservation of elastin and decreased production of pro-inflammatory cytokines. Further studies are necessary to elucidate the mechanism by which tamsulosin attenuates abdominal aortic aneurysm pathogenesis.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Aorta Abdominal/efeitos dos fármacos , Aneurisma da Aorta Abdominal/prevenção & controle , Tansulosina/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapêutico , Animais , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/patologia , Pressão Sanguínea/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Elastina/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Elastase Pancreática/toxicidade , Tansulosina/uso terapêutico , Resultado do Tratamento
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