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1.
Biomed Pharmacother ; 118: 109161, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31545223

RESUMO

This study investigated the value of using ultrasound-targeted microbubble destruction (UTMD) to deliver an IL-8 monoclonal antibody to inhibit the inflammatory response and increase plaque stability in a rabbit model of atherosclerosis (AS). An abdominal aortic atherosclerotic plaque model was established in sixty 4-week-old male New Zealand rabbits. The rabbits were fed a high-fat diet for 12 weeks. On the 12th week, the abdominal aorta was subjected to both balloon-induced mechanical injury and bovine serum albumin-induced immunological injury. After these injuries were established, the rabbits were fed a high-fat diet for 8 additional weeks. On the 20th week, the rabbits were divided into three groups: the pretreatment (PT) group, the control group, and the IL-8 group. The ultrasonic parameters and histological data associated with the plaques from the PT group were acquired on the 20th week after targeted contrast-enhanced ultrasonography (CEUS) was performed. The rabbits in the IL-8 and control groups received targeted CEUS and UTMD every 2 weeks. A targeted contrast agent carrying IL-8 monoclonal antibody was used for the IL-8 group, whereas normal saline was used for the control group. The rabbits in these two groups underwent the same procedure four times beginning during the 20th week. On the 26th week after UTMD, ultrasonic parameters and histological data were collected. The peak intensity (PI), microvessel density (MVD), and macrophage count of the PT group were significantly higher than those of both the control and IL-8 groups (P < 0.05). Additionally, these three parameters were higher in the control group than in the IL-8 group (P < 0.05). The two-dimensional (2D) ultrasonic parameters, including the maximum thickness of the plaque and the intima-media thickness (IMT), did not differ significantly among the three groups (P > 0.05). PI, MVD, and macrophage count were positively correlated with each other (r=0.564, r=0.6034, and r=0.536, respectively; P<0.05). UTMD-delivered IL-8 monoclonal antibodies alleviate inflammation within atherosclerotic plaques. UTMD is a novel and effective method for plaque stabilization.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Aorta Abdominal/diagnóstico por imagem , Interleucina-8/imunologia , Microbolhas , Placa Aterosclerótica/tratamento farmacológico , Ondas Ultrassônicas , Animais , Anticorpos Monoclonais/administração & dosagem , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/imunologia , Meios de Contraste , Dieta Hiperlipídica , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Masculino , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/imunologia , Coelhos , Ultrassonografia
2.
ACS Appl Mater Interfaces ; 11(18): 16402-16411, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-30998317

RESUMO

Fully integrated hydrogel channels were fabricated via interfacial bioorthogonal cross-linking, a diffusion-controlled method for the creation and patterning of synthetic matrices based on the rapid bioorthogonal reaction between s-tetrazines (Tz) and trans-cyclooctene (TCO) dienophiles. Injecting an aqueous solution of a bisTCO cross-linker into a reservoir of tetrazine-modified hyaluronic acid (HA-Tz), while simultaneously drawing the syringe needle through the reservoir, yielded a cross-linked hydrogel channel that was mechanically robust. Fluorescent tags and biochemical signals were spatially patterned into the channel wall through time-dependent perfusion of TCO-conjugated molecules into the lumen of the channel. Different cell populations were spatially encapsulated in the channel wall via temporal alteration of cells in the HA-Tz reservoir. The interfacial approach enabled the spatial patterning of vascular cells, including human abdominal aorta endothelial cells, aortic vascular smooth muscle cells, and aortic adventitial fibroblasts, into the hydrogel channels with high viability and proper morphology in the anatomical order found in human arteries. The bioorthogonal platform does not rely on external triggers and represents the first step toward the engineering of functional and implantable arteries.


Assuntos
Aorta Abdominal/crescimento & desenvolvimento , Células Endoteliais/efeitos dos fármacos , Hidrogéis/farmacologia , Músculo Liso Vascular/crescimento & desenvolvimento , Aorta/efeitos dos fármacos , Aorta/crescimento & desenvolvimento , Aorta Abdominal/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Reagentes para Ligações Cruzadas/química , Ciclo-Octanos/química , Células Endoteliais/patologia , Fibroblastos/efeitos dos fármacos , Humanos , Hidrogéis/síntese química , Hidrogéis/química , Músculo Liso Vascular/efeitos dos fármacos , Tetrazóis/química , Engenharia Tecidual/tendências
3.
Eur J Pharmacol ; 851: 133-143, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30797787

RESUMO

Rosiglitazone, a PPAR-γ agonist, possesses anti-fibritic effect; however, its inhibitory effect on paraquat (PQ)-induced pulmonary fibrosis is not completely understood. Here, we investigated the inhibitory effect of rosiglitazone on PQ-induced acute pulmonary fibrosis in rats and its underlying mechanism. Male Sprague-Dawly rats were administered a single intraperitoneal injection of 30 mg/kg PQ and euthanised 7, 14, 21, and 28 days after PQ poisoning. PQ-induced pulmonary fibrosis was most obvious on day 28. Male Sprague-Dawly rats were exposed either against distilled water as control groups or PQ (30 mg/kg, i.p.) as test groups. The control groups were nominated as NC group (without treatment), RSG group (only treatment with rosiglitazone, 10 mg/kg/d), and GW group (only treatment with GW9662, a PPAR-γ antagonist, 1 mg/kg/d). The test groups were nominated as PQ group (PQ exposed without treatment), PQ + RSG group (treatment with rosiglitazone), and PQ + RSG + GW group (treatment with rosiglitazone and GW9662). Rosiglitazone was able to recover the PQ-induced decrease in arterial oxygen partial pressure (PaO2), increase in the wet-to-dry (W/D) lung tissue weight ratio and lung fibrosis score. Rosiglitazone inhibited the PQ-induced reduction in protein and mRNA levels of PPAR-γ and PTEN and elevation in protein and mRNA levels of TGF-ß1 and α-SMA. GW9662 administration antagonized the effect of rosiglitazone. These data suggest that rosiglitazone attenuated PQ-induced pulmonary fibrosis by upregulateing PTEN and downregulating TGF-ß1 expression in a PPAR-γ dependent manner.


Assuntos
PPAR gama/metabolismo , Paraquat/envenenamento , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Rosiglitazona/farmacologia , Actinas/genética , Animais , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hidroxiprolina/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Oxigênio/metabolismo , PPAR gama/genética , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologia , Ratos , Ratos Sprague-Dawley , Rosiglitazona/uso terapêutico , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
4.
Toxicol Mech Methods ; 29(3): 211-218, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30480468

RESUMO

Incense smoke is reported to increase cardiovascular disease (CVD) risk in exposed individuals. However, the mechanism underlying the toxic effect of incense smoke on cardiovascular system is unclear. To test this, we chronically exposed male albino rats to two different types of Arabian incense smoke and studied their effects on oxidative stress, inflammation, and endothelial function. Rats exposed to either of incense smoke showed a significant increase in malondialdehyde (MDA) and a significant decline in superoxide dismutase (SOD) and reduced glutathione (GSH). Endothelial functional marker, nitric oxide (NO) was significantly decreased while endothelin-1 was significantly increased in rats exposed to both the incense types. Incense smoke exposure also led to a significant increase in chemokines and inflammatory mediators including monocyte chemoattractant protein-1 (MCP-1), granulocyte-macrophage-colony stimulating factor (GM-CSF), regulated on activation normal T cell expressed and secreted (RANTES), interleukin-4 (IL-4), C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-α). Besides, incense smoke-exposed rats demonstrated a significant increase in the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecules-1 (VCAM-1), and E-selectin. Importantly, cessation of incense smoke exposure for 30 days led to a significant reversal in the levels of all the studied markers. Collectively, this study describes oxidative stress, endothelial dysfunction, and inflammation as possible underlying mechanisms in the toxic effects of incense smoke on increased CVD risk in exposed individuals. Findings also underscore that avoiding incense smoke exposure may have beneficial health effects.


Assuntos
Aorta Abdominal/efeitos dos fármacos , Citocinas/sangue , Endotélio Vascular/efeitos dos fármacos , Exposição por Inalação/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Fumaça/efeitos adversos , Animais , Aorta Abdominal/imunologia , Aorta Abdominal/metabolismo , Biomarcadores/sangue , Moléculas de Adesão Celular/genética , Endotelina-1/metabolismo , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Masculino , Óxido Nítrico/metabolismo , Estresse Oxidativo/imunologia , Ratos Wistar
6.
Lipids Health Dis ; 17(1): 272, 2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30497486

RESUMO

BACKGROUND: To investigate the effects of a Chinese herbal medicine Fufang-Zhenzhu Tiaozhi Capsule (FTZ) on restenosis and elucidate the mechanism of action. METHODS: A restenosis model was established by balloon rubbing the endothelium of the abdominal aorta followed by high fat diet. Rabbits were divided into blank control group, restenosis group, FTZ group (0.66 mg/kg/day), atorvastatin group (5 mg/kg/day) and FTZ + atorvastatin group (n = 8). Vascular stenosis was analyzed by X-ray. Serum levels of chemokines and cytokines interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-12 (IL-12), C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1) were measured by ELISA. The levels of NF-κB, IκB-α, P-IκBα, IKK-α, and P-IKKα/ß from injured abdominal arteries were detected by Western blotting. RESULTS: Restenosis was induced successfully via abdominal artery balloon injuries and high fat diet. Restenosis was significantly decreased in FTZ group compared with restenosis group (P < 0.05). FTZ group had markedly reduced serum lipid levels (P < 0.05). In addition, the levels of TNF-α, IL-1, IL-6, IL-8, IL-12, ICAM-1 and MCP-1 decreased by FTZ treatment (P < 0.05). The expression of NF-κB in the atherosclerotic lesions was significantly attenuated in FTZ group (P < 0.05). CONCLUSION: FTZ could reduce restenosis via reducing NF-κB activity and inflammatory factor expression within the atherosclerotic lesion in a rabbit restenosis model. FTZ may be a new therapeutic agent for restenosis.


Assuntos
Aterosclerose/tratamento farmacológico , Reestenose Coronária/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Inflamação/tratamento farmacológico , Animais , Aorta Abdominal/efeitos dos fármacos , Aterosclerose/genética , Aterosclerose/fisiopatologia , Atorvastatina , Proteína C-Reativa/genética , Quimiocina CCL2/genética , Reestenose Coronária/genética , Reestenose Coronária/fisiopatologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Endotélio/efeitos dos fármacos , Endotélio/fisiopatologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/genética , Inflamação/fisiopatologia , Interleucina-1/genética , Interleucina-12/genética , Interleucina-6/genética , Interleucina-8/genética , NF-kappa B/genética , Coelhos , Fator de Necrose Tumoral alfa/genética
7.
PLoS One ; 13(12): e0207683, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30521536

RESUMO

Atherosclerosis-predominant vasculopathy is a common complication of diabetes with high morbidity and high mortality, which is ruining the patient's daily life. As is known to all, traditional Chinese medicine (TCM) SHENQI compound and western medicine rosiglitazone play an important role in the treatment of diabetes. In particular, SHENQI compound has a significant inhibitory effect on vascular lesions. Here, to explore and compare the therapeutic mechanism of SHENQI compound and rosiglitazone on diabetic vasculopathy, we first built 7 groups of mouse models. The behavioral, physiological and pathological morphological characteristics of these mice showed that SHENQI compound has a more comprehensive curative effect than rosiglitazone and has a stronger inhibitory effect on vascular lesions. While rosiglitazone has a more effective but no significant effect on hypoglycemic. Further, based on the gene expression of mice in each group, we performed differential expression analysis. The functional enrichment analysis of these differentially expressed genes (DEGs) revealed the potential pathogenesis and treatment mechanisms of diabetic angiopathy. In addition, we found that SHENQI compound mainly exerts comprehensive effects by regulating MCM8, IRF7, CDK7, NEDD4L by pivot regulator analysis, while rosiglitazone can rapidly lower blood glucose levels by targeting PSMD3, UBA52. Except that, we also identified some pivot TFs and ncRNAs for these potential disease-causing DEG modules, which may the mediators bridging drugs and modules. Finally, similar to pivot regulator analysis, we also identified the regulation of some drugs (e.g. bumetanide, disopyramide and glyburide etc.) which have been shown to have a certain effect on diabetes or diabetic angiopathy, proofing the scientific and objectivity of this study. Overall, this study not only provides an in-depth comparison of the efficacy of SHENQI compound and rosiglitazone in the treatment of diabetic vasculopathy, but also provides clinicians and drug designers with valuable theoretical guidance.


Assuntos
Angiopatias Diabéticas/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Rosiglitazona/uso terapêutico , Animais , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/patologia , Fármacos Cardiovasculares/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Angiopatias Diabéticas/genética , Angiopatias Diabéticas/patologia , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Fitoterapia , Transdução de Sinais/genética
8.
Int J Nanomedicine ; 13: 7819-7834, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30538461

RESUMO

Background: The harmful effects following the release of nanomaterials into environment are of great concern today. Purpose: In this study, subacute effect due to co-exposure to low-dose silica nanoparticles (SiNPs) and lead acetate (Pb) on cardiovascular system was detected in Sprague Dawley male rats. Materials and Methods: Histopathological and ultrastructural changes of heart, aortic arch and abdominal aorta were detected. Blood routine and blood biochemistry examinations were used to show the changes of blood components. The fibrinolytic and plasmin factors, inflammation-related factors and myocardial-related enzyme in serum were analysised by ELISA and Western blot assay. Results: Histopathological and ultrastructural examination of heart, aortic arch, and abdominal aorta showed that serious damage occurred in co-exposure group (n=6/group). Blood routine examination showed that leukocytosis and thrombocytopenia increased markedly, while changes in the erythrocyte count were not obvious in the co-exposure group. The expression of alanine transaminase (ALT) decreased obviously in co-exposure group, while no significant changes were noted in the expression of aspartate aminotransferase (AST), cholesterol (CHO), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) in the co-exposure group on blood biochemistry analysis. In addition, data from ELISA analysis showed that the levels of fibrinolytic and plasmin factors, including thrombin time (TT), prothrombin time (PT), activated partial thromboplastin time (APTT), tissue-type plasminogen activator (t-PA), tissue factor pathway inhibitor (TFPI), and antithrombin III (AT III), were decreased, while those of human fibrinogen (FIB) and D-dimer (D2D) increased significantly in the co-exposure group. Moreover, the myocardial-related enzyme in serum, tested by ELISA, and cardiovascular-related protein expression of atrial natriuretic peptide and brain natriuretic peptide, tested by Western blot assay, was increased in the heart. Furthermore, the expression of inflammation factors such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) was increased in heart tissue subjected to combined exposure, which was manifested by Western blot assay, while the protein levels of angiotensin II (ANG II) and endothelin 1 were (ET-1) elevated in blood vessels in the co-exposure group. Conclusion: In conclusion, the major interactions involved in subacute toxicity due to co-exposure to low doses of SiNPs and Pb on cardiovascular system were expected to be additive and synergistic in nature. Co-exposure to SiNPs and Pb could aggravate the cardiovascular toxicity via endothelial damage, hypercoagulation, and cardiac injury in vivo.


Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Nanopartículas/toxicidade , Compostos Organometálicos/toxicidade , Dióxido de Silício/toxicidade , Testes de Toxicidade Aguda , Animais , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/patologia , Coagulação Sanguínea/efeitos dos fármacos , Sistema Cardiovascular/patologia , Masculino , Miocárdio/ultraestrutura , Nanopartículas/ultraestrutura , Proteínas/metabolismo , Ratos Sprague-Dawley
9.
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
10.
PLoS One ; 13(10): e0205366, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30312321

RESUMO

Hemodynamics may play an essential role in the initiation and progression of abdominal aortic aneurysm (AAA). We aimed to study the mechanism of self-healing process by the changes of hemodynamics and pathology in an enlarging AAA in rabbits. Seventy-two rabbits were randomly divided into three groups. Rabbits underwent extrinsic coarctation and received a 10-minute elastase incubation in Group A and Group B. Absorbable suture used in Group A was terminated by balloon dilation at week 4. Diameter was measured after 1, 3, 5, and 15 weeks, computational fluid dynamics analysis was performed at week 3 and week 15. Rabbits were sacrificed after 1, 5, and 15 weeks for pathological and quantitative studies. The higher velocity magnitude, intensified bulk flow and obvious vortex formation were observed in Group A at week 3 instead of week 15. Both low wall shear stress and high relative residence time increased in Group B, however, high oscillatory shear index had relatively less increase compared with Group A. Aortic diameter reached a plateau at 5 weeks in Group A, which was significantly lower than in week 15 in Group B. Intimal hyperplasia, intima-media thickness increased significantly in Group A at week 5, significantly higher than in week 15 in Group B. Marked destruction of elastin fibers and smooth muscle cells occurred at week 1, and increased significantly at week 15 in Group A. Aneurysm exhibited strong expression of matrix metalloproteinase 9 and mouse anti-rabbit macrophage 11 at week 1, and showed a tendency to decrease. Matrix metalloproteinase 2 expression decreased significantly in Group B at week 15 compared with week 5 and Group A. In conclusion, the self-healing of rabbit AAA may attributed to the regeneration of smooth muscle cells. The turbulence flow caused by coarctation is associated with continuous growth of rabbit AAA and prevents the self-healing phenomenon.


Assuntos
Aneurisma da Aorta Abdominal/patologia , Hemodinâmica , Animais , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/metabolismo , Aorta Abdominal/fisiopatologia , Aneurisma da Aorta Abdominal/fisiopatologia , Artérias Carótidas/fisiologia , Espessura Intima-Media Carotídea , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Elastase Pancreática/farmacologia , Coelhos , Regulação para Cima/efeitos dos fármacos
11.
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
12.
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
13.
Physiol Rep ; 6(18): e13878, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30230255

RESUMO

Abdominal aortic aneurysm (AAA) is a progressive disease that has an increasing prevalence with aging, but no effective pharmacological therapy to attenuate AAA progression is currently available. We reported that the prostaglandin E receptor EP4 plays roles in AAA progression. Here, we show the effect of CJ-42794, a selective EP4 antagonist, on AAA using two mouse models (angiotensin II- and CaCl2 -induced AAAs) and human aortic smooth muscle cells isolated from AAA tissue. Oral administration of CJ-42794 (0.2 mg/kg per day) for 4 weeks significantly decreased AAA formation in ApoE-/- mice infused with angiotensin II (1 µg/kg per min), in which elastic fiber degradation and activations of matrix metalloproteinase (MMP)-2 and MMP-9 were attenuated. Interleukin-6 (IL-6) proteins were highly expressed in the medial layer of angiotensin II-induced mouse AAA tissues, whereas this expression was significantly decreased in mice treated with CJ-42794. AAA formation induced by periaortic CaCl2 application in wild-type mice was also reduced by oral administration of CJ-42794 for 4 weeks. After oral administration of CJ-42794 beginning 2 weeks after periaortic CaCl2 application and continuing for an additional 4 weeks, the aortic diameter and elastic fiber degradation grade were significantly smaller in CJ-42794-treated mice than in untreated mice. Additionally, in smooth muscle cells isolated from human AAA tissues, stimulation of CJ-42794 inhibited PGE2 -induced IL-6 secretion in a dose-dependent manner and decreased PGE2 -induced MMP-2 activity. These data suggest that inhibition of EP4 has the potential to be a pharmacological strategy for attenuation of AAA progression.


Assuntos
Aneurisma da Aorta Abdominal/tratamento farmacológico , Aneurisma da Aorta Abdominal/metabolismo , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Compostos de Sulfonilureia/uso terapêutico , Animais , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/patologia , Apolipoproteínas E/deficiência , Células Cultivadas , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Compostos de Sulfonilureia/farmacologia
14.
Mol Med Rep ; 18(3): 3421-3428, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30066924

RESUMO

Research into inflammation during abdominal aortic aneurysm (AAA) formation remains inconclusive. The present study aimed to demonstrate the temporal and spatial distribution of inflammatory cytokines, and to confirm the effect of peroxisome proliferator­activated receptor γ (PPARγ) on the incidence of AAA formation and the distribution of inflammation in the disease process. Male apolipoprotein E­/­ mice were randomly divided into eight groups: Angiotensin II (Ang­II)­only 7, 14, 21, 28 and 42 days groups, Ang­II with rosiglitazone (RGZ) 28 and 42 days groups, and the saline control 42 days group. The early stage was defined as between 7 and 21 days, and the late stage as between 28 and 42 days. Incidences of early rupture and late rupture, aneurysm formation and the maximum diameters of the aorta were recorded. Suprarenal abdominal aortic tissues were collected for histological analysis, and western blotting was performed to reveal the distribution of inflammation. Treatment with Ang­II caused a significant dilation of the aorta in the late stage; however, this was not observed in the early stage. RGZ reduced the maximum diameters in the late stage. With the pathological process alterations, the inflammatory type shifted. Regarding temporal distribution, the tumor necrosis factor (TNF)­α expression level was increased over time, and the interleukin (IL)­10 expression level significantly decreased. When considering the spatial distribution, TNF­α was expressed dominantly in the aneurysmal body and IL­10 was dominant in the aneurysmal neck in the late stage. The PPARγ agonist RGZ may reduce the expression of TNF­α in the late stage and increase the expression level of IL­10, maintaining the TNF­α or IL­10 expression levels at the same levels as in the early stage. Aortic inflammation during AAA formation is dynamic. Protective anti­inflammatory cytokines are upregulated in the early 'compensatory stage'; however, pro­inflammatory cytokines are dominant in the late 'decompensatory stage'. PPARγ is likely to continue to upregulate the expression of anti­inflammatory cytokines, extend the 'compensatory stage', and decelerate the process of AAA development and rupture.


Assuntos
Aneurisma da Aorta Abdominal/etiologia , Aneurisma da Aorta Abdominal/metabolismo , Inflamação/complicações , Inflamação/metabolismo , PPAR gama/metabolismo , Tiazolidinedionas/farmacologia , Angiotensina II/farmacologia , Animais , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/patologia , Ruptura Aórtica , Apolipoproteínas E/deficiência , Modelos Animais de Doenças , Inflamação/genética , Inflamação/imunologia , Masculino , Camundongos , Camundongos Knockout , Modelos Biológicos , PPAR gama/agonistas , Rosiglitazona , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/metabolismo , Vasodilatadores/farmacologia
16.
Bull Exp Biol Med ; 165(2): 264-268, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29926276

RESUMO

We have previously developed a polycaprolactone (PCL) vascular graft with incorporated vascular endothelial growth factor (VEGF). Functioning of the PCL/VEGF graft in rat circulatory system over 1, 3 and 6 months after implantation into abdominal aorta was tested. Graft patency and formation of vascular wall elements were assessed histologically and by immunofluorescence staining for von Willebrand factor, CD31, CD34, and collagens I and IV and DAPI staining. Local application of VEGF promoted endothelialization and improved patency of the graft. The wall of the PCL/VEGF graft underwent remodeling due to active cellular infiltration and the extracellular matrix deposition.


Assuntos
Prótese Vascular , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Poliésteres/química , Fatores de Crescimento do Endotélio Vascular/farmacologia , Animais , Aorta Abdominal/citologia , Aorta Abdominal/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/fisiologia , Endotélio Vascular/citologia , Endotélio Vascular/fisiologia , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Masculino , Ratos , Ratos Wistar , Enxerto Vascular , Remodelação Vascular/efeitos dos fármacos
17.
Diab Vasc Dis Res ; 15(5): 367-374, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29874945

RESUMO

INTRODUCTION: Diabetes mellitus appears to be negatively associated with abdominal aortic aneurysm; however, the mechanisms underlying this relationship remain poorly understood. The aim of this article is to provide a comprehensive review of the currently understood biological pathways underlying this relationship. METHODS: A review of the literature ('diabetes' OR 'hyperglycaemia' AND 'aneurysm') was performed and relevant studies grouped into biological pathways. RESULTS: This review identified a number of biological pathways through which diabetes mellitus may limit the presence, growth and rupture of abdominal aortic aneurysms. These include those influencing extracellular matrix volume, extracellular matrix glycation, the formation of advanced glycation end-products, inflammation, oxidative stress and intraluminal thrombus biology. In addition, there is an increasing evidence to suggest that the medications used to treat diabetes can also limit the development and progression of abdominal aortic aneurysms. CONCLUSION: The negative association between diabetes and abdominal aortic aneurysm is robust. Future studies should attempt to target the pathways identified in this review to develop novel therapeutic agents aimed at slowing or even halting aneurysm progression.


Assuntos
Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/etiologia , Diabetes Mellitus , Remodelação Vascular , Animais , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/sangue , Aneurisma da Aorta Abdominal/diagnóstico , Aneurisma da Aorta Abdominal/prevenção & controle , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Mellitus/sangue , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/tratamento farmacológico , Dilatação Patológica , Progressão da Doença , Matriz Extracelular/metabolismo , Produtos Finais de Glicação Avançada/sangue , Humanos , Hipoglicemiantes/uso terapêutico , Mediadores da Inflamação/metabolismo , Estresse Oxidativo , Fatores de Risco , Remodelação Vascular/efeitos dos fármacos
18.
Life Sci ; 207: 72-79, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-29852188

RESUMO

The biguanide metformin (MET) has been used during pregnancy for treatment of polycystic ovary syndrome and gestational diabetes. MET crosses the placenta and maternal treatment can expose the progeny to this drug during important phases of body development. Direct vascular protective effects have been described with the treatment of metformin. Nevertheless, it is unclear whether intrauterine exposure to metformin is safe for the vascular system of offspring. Thus, the present study aimed to investigate the intrinsic effects of metformin exposure in utero in the offspring abdominal aorta reactivity, in the presence and absence of perivascular adipose tissue (PVAT) and endothelium. For this, Wistar rats were treated with metformin 293 mg/kg/day (MET) or water (CTR) by gavage during the gestational period. The abdominal aorta reactivity to phenylephrine, acetylcholine, and sodium nitroprusside was evaluated in male adult offspring. It was observed that abdominal aorta relaxation was similar between MET and CTR groups in the presence or absence of PVAT. In addition, the contraction to phenylephrine was similar between MET and CTR groups in the presence and absence of PVAT and endothelium. Therefore, metformin exposure during pregnancy had no intrinsic effect on the offspring abdominal aorta PVAT and endothelial function, demonstrating it to be safe to the vascular system of the offspring.


Assuntos
Aorta Abdominal/fisiologia , Exposição Materna , Metformina/farmacologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/fisiologia , Animais , Aorta Abdominal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/fisiologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Feminino , Masculino , Nitroprussiato/farmacologia , Gravidez , Prenhez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos Wistar , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
19.
Biomed Pharmacother ; 104: 550-557, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29800919

RESUMO

BACKGROUND: Particulate matter 2.5 (PM2.5) has proven to be associated with morbidity and mortality from cardiovascular diseases. However, whether PM2.5 could promote the formation of abdominal aortic aneurysm (AAA) is unclear. Present study aimed to explore the relationship between PM2.5 exposure and AAA development. METHODS: Ang Ⅱ-infused apoe-/- mice were treated with PM2.5 or saline by intranasal instillation. Four weeks later, histological and immunohistological analyses were used to evaluate the effect of PM2.5 on AAA formation. Human aortic smooth muscle cells (HASMCs) were also employed to further analyze the adverse effect of PM2.5 in vitro. RESULTS: We found that PM2.5 could significantly increase the AAA incidence, the maximal abdominal aortic diameter and could promote the degradation of elastin. Additionally, the expression of senescence markers, P21 and P16 were also enhanced after PM2.5 exposure. We also found that PM2.5 significantly increased the AAA related pathological changes, MMP2 and MCP-1 expression in HASMCs. Meanwhile, PM2.5 could increase the expression of senescence markers P21, P16 and SA-ß-gal activity, also the reactive oxygen species levels in vitro. CONCLUSIONS: PM2.5 promoted the formation of AAA in an Ang Ⅱ-induced AAA model. The underlying mechanism might be cellular senescence after PM2.5 exposure.


Assuntos
Angiotensina II/metabolismo , Aorta Abdominal/efeitos dos fármacos , Aneurisma da Aorta Abdominal/induzido quimicamente , Apolipoproteínas E/metabolismo , Material Particulado/efeitos adversos , Animais , Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/metabolismo , Biomarcadores/metabolismo , Linhagem Celular , Quimiocina CCL2/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Modelos Animais de Doenças , Elastina/metabolismo , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Espécies Reativas de Oxigênio/metabolismo , beta-Galactosidase/metabolismo
20.
Diabetes ; 67(8): 1549-1560, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29794241

RESUMO

Obesity increases the risk of vascular diseases, including aortic aneurysm (AA). Perivascular adipose tissue (PVAT) surrounding arteries are altered during obesity. However, the underlying mechanism of adipose tissue, especially PVAT, in the pathogenesis of AA is still unclear. Here we showed that angiotensin II (AngII) infusion increases the incidence of AA in leptin-deficient obese mice (ob/ob) and high-fat diet-induced obese mice with adventitial inflammation. Furthermore, transcriptome analysis revealed that platelet-derived growth factor-D (PDGF-D) was highly expressed in the PVAT of ob/ob mice. Therefore, we hypothesized that PDGF-D mediates adventitial inflammation, which provides a direct link between PVAT dysfunction and AA formation in AngII-infused obese mice. We found that PDGF-D promotes the proliferation, migration, and inflammatory factors expression in cultured adventitial fibroblasts. In addition, the inhibition of PDGF-D function significantly reduced the incidence of AA in AngII-infused obese mice. More importantly, adipocyte-specific PDGF-D transgenic mice are more susceptible to AA formation after AngII infusion accompanied by exaggerated adventitial inflammatory and fibrotic responses. Collectively, our findings reveal a notable role of PDGF-D in the AA formation during obesity, and modulation of this cytokine might be an exploitable treatment strategy for the condition.


Assuntos
Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/etiologia , Gordura Intra-Abdominal/metabolismo , Linfocinas/metabolismo , Obesidade/fisiopatologia , Fator de Crescimento Derivado de Plaquetas/metabolismo , Túnica Adventícia/efeitos dos fármacos , Túnica Adventícia/imunologia , Túnica Adventícia/metabolismo , Túnica Adventícia/patologia , Angiotensina II/administração & dosagem , Angiotensina II/efeitos adversos , Animais , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Benzimidazóis/farmacologia , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Implantes de Medicamento , Regulação da Expressão Gênica/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/imunologia , Gordura Intra-Abdominal/patologia , Linfocinas/agonistas , Linfocinas/antagonistas & inibidores , Linfocinas/genética , Masculino , Camundongos , Camundongos Mutantes , Camundongos Transgênicos , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Especificidade de Órgãos , Fator de Crescimento Derivado de Plaquetas/agonistas , Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Fator de Crescimento Derivado de Plaquetas/genética , Quinolinas/farmacologia , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Gordura Subcutânea Abdominal/efeitos dos fármacos , Gordura Subcutânea Abdominal/imunologia , Gordura Subcutânea Abdominal/metabolismo , Gordura Subcutânea Abdominal/patologia , Análise de Sobrevida
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