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1.
Toxicol Lett ; 316: 27-34, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31513887

RESUMO

OBJECTIVE: Atherosclerosis is an autoimmune inflammatory disease that is closely associated with long-term exposure to fine particulate matter (PM2.5). CD4+CD25+Foxp3+ regulatory T cells (Tregs) play a critical role in the regulation of T cell-mediated immune responses, and the depletion of CD4+CD25+Foxp3+ Tregs has been thought to play a prominent role in atherosclerosis. Therefore, we investigated the association between the CD4+CD25+Foxp3+ Tregs population and atherosclerotic development in ApoE-/- mice exposed to PM2.5. METHODS: We employed a real-world system to subject 40 ApoE-/- mice to ambient inhalation of PM2.5 (PM2.5 group, n = 20) or filtered air (FA group, n = 20) for 12 weeks. PM2.5 source apportionment, atherosclerotic lesions within aorta, lipid deposition and plaque accumulation in whole artery, serum level of inflammatory factors and lipid profiles, CD4+CD25+Foxp3+ Tregs population in splenocytes, Foxp3 protein and mRNA expressions in descending aorta and spleen were quantified, respectively. RESULTS: The daily average concentration of PM2.5 was 57.4 ± 25.6 µg/m3. Atherosclerotic lesions within aorta, lipid deposition and plaque accumulation in whole artery, serum levels of IL-6, TNF-α, TC and LDL-C in the PM2.5 group increased significantly compared to the FA group. Whereas, serum levels of IL-10 and TGF-ß, CD4+CD25+Foxp3+ Tregs population in splenocytes, Foxp3 protein and mRNA expressions in descending aorta and spleen in the PM2.5 group decreased significantly compared to the FA group. CONCLUSION: These results suggest that PM2.5 could accelerate the development of atherosclerosis in ApoE-/- mice, which is related to CD4+CD25+Foxp3+ Tregs down-regulation, as well as lipid deposition and systemic inflammation.


Assuntos
Aorta/efeitos dos fármacos , Doenças da Aorta/induzido quimicamente , Aterosclerose/induzido quimicamente , Fatores de Transcrição Forkhead/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Material Particulado/toxicidade , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Aorta/imunologia , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/sangue , Doenças da Aorta/imunologia , Doenças da Aorta/patologia , Aterosclerose/sangue , Aterosclerose/imunologia , Aterosclerose/patologia , Biomarcadores/sangue , LDL-Colesterol/sangue , Citocinas/sangue , Modelos Animais de Doenças , Progressão da Doença , Fatores de Transcrição Forkhead/imunologia , Predisposição Genética para Doença , Mediadores da Inflamação/sangue , Subunidade alfa de Receptor de Interleucina-2/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Tamanho da Partícula , Fenótipo , Placa Aterosclerótica , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Fatores de Tempo
2.
J Thorac Cardiovasc Surg ; 157(1): 109-119.e2, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30528439

RESUMO

OBJECTIVES: Fluoroquinolone (FQ) antibiotics are associated with adverse aortic clinical events. We assessed human aortic myofibroblast-mediated extracellular matrix (ECM) dysregulation as a possible cellular mechanism underlying FQ-associated aortopathy. METHODS: Human aortic myofibroblasts were isolated from patients with aortopathy undergoing elective ascending aortic resection (N = 9). The capacity for extracellular matrix degradation in cells exposed to FQ was assessed by multiplex analysis of secreted matrix metalloproteinases relative to tissue inhibitors of matrix metalloproteinases (TIMPs). Direct evaluation of extracellular matrix degradation was investigated in human aortic cells using a 3-dimensional gelatin-fluorescein isothiocyanate fluorescence microgel assay. Aortic cellular collagen-1 expression following FQ exposure was determined by immunoblotting and immunofluorescent staining. Cell apoptosis, necrosis, and metabolic viability was determined by annexin-V, propidium iodide staining, and water-soluble tetrazolium salt (WST1) assay. RESULTS: FQ exposure significantly decreased aortic cell TIMP-1 (P = .004) and TIMP-2 (P = .0004) protein expression compared with vehicle control. The ratio of matrix metalloproteinase-9/TIMP-2 was increased suggesting an increased capacity for extracellular matrix degradation (P = .01). In collagen gels, we show a trend toward increased aortic myofibroblast-mediated collagen fiber degradation with FQ exposure (P = .09). Similarly, FQ exposure attenuated collagen-1 expression as assessed by immunoblotting (P = .002) and immunofluorescence (P = .02). Cell apoptosis, necrosis, and metabolic viability was not significantly influenced by FQ exposure. CONCLUSIONS: For the first time, we document a putative mechanism underlying FQ-associated aortopathy whereby decreased TIMP expression with impaired compensatory collagen-1 expression results in human aortic myofibroblast-mediated extracellular matrix dysregulation. These novel data may provide a cellular and molecular mechanism to explain the established clinical association between FQ exposure and acute aortic events.


Assuntos
Aorta/citologia , Doenças da Aorta/induzido quimicamente , Matriz Extracelular/efeitos dos fármacos , Fluoroquinolonas/efeitos adversos , Miofibroblastos/efeitos dos fármacos , Aorta/efeitos dos fármacos , Aorta/fisiopatologia , Doenças da Aorta/fisiopatologia , Apoptose/efeitos dos fármacos , Células Cultivadas , Matriz Extracelular/fisiologia , Feminino , Imunofluorescência , Humanos , Immunoblotting , Masculino , Pessoa de Meia-Idade , Miofibroblastos/fisiologia , Inibidores Teciduais de Metaloproteinases/antagonistas & inibidores
3.
Atherosclerosis ; 277: 80-89, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30176568

RESUMO

BACKGROUND AND AIMS: Atherosclerosis is critically fueled by vascular inflammation through oxidized lipids and inflammatory cytokines such as tumor necrosis factor (TNF)-α. Genetic disruption of Tnf-α reduces atherosclerosis in experimental mouse models. However, less is known about the therapeutic potential of Tnf-α blockage by pharmacological inhibitors such as monoclonal antibodies, which are already approved for several inflammatory disorders in patients. Therefore, we investigated the effect of pharmacological TNF-α inhibition on plaque development in experimental atherosclerosis. RESULTS: 10 week old male Ldlr-/- mice were divided into 4 groups (n = 7-10) and fed a high fat, high cholesterol diet for 6 and 12 weeks. Simultaneously, the mouse-specific anti-Tnf-α monoclonal antibody CNTO5048 (CNT) or a control IgG was administered. RESULTS: CNT reduced circulating inflammatory markers without affecting body weight and glucose metabolism. Unexpectedly, CNT treatment increased plasma triglyceride levels and pro-atherogenic very-low-density lipoprotein (VLDL) cholesterol as well as plaque burden in the thoracoabdominal aorta and in the aortic root. In addition, we observed decreased smooth muscle cell content in the lesions and a trend towards reduced collagen deposition upon Tnf-α inhibition. Furthermore, inflammatory gene expression in the aortic arch was increased following Tnf-α inhibitor treatment. CONCLUSIONS: Although up to 12-week pharmacological inhibition of TNF-α in Ldlr-/- mice diminishes systemic inflammation, experimental plaque burden and vascular inflammatory gene expression are increased, while markers of plaque stability decrease. These observations may be explained by the development of a pro-atherogenic plasma lipid profile.


Assuntos
Anti-Inflamatórios/toxicidade , Anticorpos Monoclonais/toxicidade , Aorta/efeitos dos fármacos , Doenças da Aorta/induzido quimicamente , Aterosclerose/induzido quimicamente , Placa Aterosclerótica , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Linhagem Celular , Dieta Hiperlipídica , Modelos Animais de Doenças , Progressão da Doença , Predisposição Genética para Doença , Lipídeos/sangue , Masculino , Camundongos Knockout , Fenótipo , Receptores de LDL/deficiência , Receptores de LDL/genética , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismo
4.
Cardiovasc Res ; 114(14): 1883-1893, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29982418

RESUMO

Aims: Immune cell function involves energy-dependent processes including growth, proliferation, and cytokine production. Since the AMP-activated protein kinase (AMPK) is a crucial regulator of intracellular energy homeostasis, its expression and activity may also affect innate and adaptive immune cell responses. Therefore, we aimed to investigate the consequences of α1AMPK deletion in myelomonocytic cells on vascular function, inflammation, and hypertension during chronic angiotensin II (ATII) treatment. Methods and results: We generated a mouse strain with α1AMPK deletion in lysozyme M+ myelomonocytic cells. Compared to controls, chronic ATII infusion (1 mg/kg/day for 7 days) lead to increased vascular oxidative stress and aggravated endothelial dysfunction in LysM-Cre+ x α1AMPKfl/fl mice. This was accompanied by an increased aortic infiltration of CD11b+F4/80+ macrophages and enhanced pro-inflammatory cytokine release (tumour necrosis factor-alpha, interferon-gamma, and interleukin-6). Mechanistically, we found that increased expression of C-C chemokine receptor 2 (CCR2) in α1AMPK deficient myelomonocytic cells facilitated their recruitment to the vascular wall. In addition, expression of the ATII receptor type 1a and the oxidative burst was increased in these cells, indicating an increased susceptibility towards pro-oxidant stimuli. Conclusions: In summary, α1AMPK deletion in myelomonocytic cells aggravates vascular oxidative stress and dysfunction by enhancing their recruitment to the vascular wall and increasing their susceptibility towards pro-oxidant stimuli. Our observations suggest that metabolic control in myelomonocytic cells has profound implications for their inflammatory phenotype and may trigger the development of vascular disease.


Assuntos
Proteínas Quinases Ativadas por AMP/deficiência , Aorta/enzimologia , Doenças da Aorta/enzimologia , Citocinas/metabolismo , Deleção de Genes , Mediadores da Inflamação/metabolismo , Macrófagos/enzimologia , Estresse Oxidativo , Vasodilatação , Proteínas Quinases Ativadas por AMP/genética , Angiotensina II , Animais , Aorta/fisiopatologia , Doenças da Aorta/induzido quimicamente , Doenças da Aorta/genética , Doenças da Aorta/fisiopatologia , Células Cultivadas , Modelos Animais de Doenças , Predisposição Genética para Doença , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Transdução de Sinais
5.
J Cardiovasc Pharmacol ; 72(6): 270-276, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29738375

RESUMO

BACKGROUND: Hypomagnesemia was identified as a strong risk factor for cardiovascular disease in patients with chronic renal failure (CRF). However, the effects of magnesium (Mg) on vascular calcification (VC) have not been fully elucidated. Thus, we aim to determine the effects of Mg citrate (MgCit) on VC in CRF rats. METHODS: Rats were divided into 5 groups: group 1 (normal diet), group 2 (normal diet with MgCit), group 3 (the VC model of CRF induced by 0.75% adenine and 0.9% phosphorus diet from day 1 to day 28), group 4 (group 3 treated with low-dose MgCit from day 1 to day 42), and group 5 (same as group 3 except the high-dose MgCit). All rats were killed at day 43 with collection of blood and aortas. Then, serum biochemical parameters, VC-related staining, calcium and P contents, alkaline phosphatase contents and activity, expression of alpha smooth muscle actin, and runt-related transcription factor 2 (RUNX2) in aortas were assessed. RESULTS: Group 3 had extensive VC. The VC degree decreased in groups 4 and 5 in a dose-depended manner with reduced calcium content, P levels, alkaline phosphatase content and activity, and protein levels of RUNX2 and increased protein levels of alpha smooth muscle actin in aortas. CONCLUSIONS: MgCit exerted a protective role in VC in adenine-induced CRF rats; thus, it may be a potential drug for the prevention of VC in patients with CRF.


Assuntos
Adenina , Aorta/efeitos dos fármacos , Doenças da Aorta/prevenção & controle , Fármacos Cardiovasculares/farmacologia , Ácido Cítrico/farmacologia , Falência Renal Crônica/tratamento farmacológico , Compostos Organometálicos/farmacologia , Fósforo na Dieta , Calcificação Vascular/prevenção & controle , Actinas/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/induzido quimicamente , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Cálcio/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Modelos Animais de Doenças , Falência Renal Crônica/induzido quimicamente , Masculino , Ratos Sprague-Dawley , Calcificação Vascular/induzido quimicamente , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia
6.
Intern Med ; 57(20): 2987-2990, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-29780110

RESUMO

A 65-year-old man was diagnosed with advanced non-small, non-squamous lung cancer. He was treated with chemotherapy containing bevacizumab as well as cisplatin and pemetrexed. After 2 courses of treatment, computed tomography revealed that his abdominal aortic artery was almost occluded by a thrombus; however, he had no ischemic symptoms. Heparin infusion and warfarin reduced the size of the arterial thrombus and the patient was subsequently treated with chemotherapy without bevacizumab. No thrombotic events occurred during the subsequent treatment. We later noticed a small organized abdominal arterial clot and calcification on a computed tomography scan taken before bevacizumab treatment. Atherosclerotic changes should be evaluated before the administration of bevacizumab.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doenças da Aorta/induzido quimicamente , Doenças da Aorta/tratamento farmacológico , Bevacizumab/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Heparina/uso terapêutico , Humanos , Masculino , Pemetrexede/efeitos adversos , Pemetrexede/uso terapêutico , Trombose/induzido quimicamente , Trombose/tratamento farmacológico , Resultado do Tratamento , Varfarina/uso terapêutico
7.
Arterioscler Thromb Vasc Biol ; 38(5): 1007-1019, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29567680

RESUMO

OBJECTIVE: Cardiovascular diseases and depression are the leading causes of disability in Western countries. Clinical data on potential cardiovascular effects of serotonin reuptake inhibitors (SSRIs), the most commonly used antidepressant drugs, are controversial. In addition to blocking serotonin reuptake transporter in the brain, SSRIs deplete the major peripheral serotonin (5-hydroxytryptamine [5-HT]) storage by inhibiting serotonin reuptake transporter-mediated uptake in platelets. In this study, we aimed to investigate the effect of chronic SSRI intake on the development of atherosclerosis. APPROACH AND RESULTS: Treatment of apolipoprotein E-deficient mice with the SSRI fluoxetine for 2, 4, or 16 weeks increased atherosclerotic lesion formation, with most pronounced effect during early plaque development. Intravital microscopy of carotid arteries revealed enhanced myeloid cell adhesion on fluoxetine treatment. Mechanistically, we found that fluoxetine augmented vascular permeability and increased chemokine-induced integrin-binding activity of circulating leukocytes. In vitro stimulation of murine blood demonstrated that fluoxetine, but not 5-HT, could directly promote ß1 and ß2 integrin activation provided C-C motif chemokine ligand 5 was also present. Similar effects were observed with the SSRI escitalopram. Enhanced C-C motif chemokine ligand 5-induced integrin activation by fluoxetine was also confirmed in a human neutrophil-like cell line. In contrast to the proatherogenic properties of fluoxetine, pharmacological inhibition of the peripheral 5-HT synthesizing enzyme tryptophan hydroxylase 1 did not promote atherosclerosis, suggesting that the proatherogenic effect of fluoxetine occurs independent of peripheral 5-HT depletion. CONCLUSIONS: SSRI intake may promote atherosclerosis and therefore potentially increase the risk for acute cardiovascular events by a mechanism that is independent of 5-HT depletion.


Assuntos
Aorta/efeitos dos fármacos , Doenças da Aorta/induzido quimicamente , Aterosclerose/induzido quimicamente , Artérias Carótidas/efeitos dos fármacos , Doenças das Artérias Carótidas/induzido quimicamente , Fluoxetina/toxicidade , Placa Aterosclerótica , Inibidores de Captação de Serotonina/toxicidade , Animais , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/sangue , Doenças da Aorta/genética , Doenças da Aorta/patologia , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/patologia , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Antígenos CD18/sangue , Permeabilidade Capilar/efeitos dos fármacos , Artérias Carótidas/metabolismo , Artérias Carótidas/patologia , Doenças das Artérias Carótidas/sangue , Doenças das Artérias Carótidas/genética , Doenças das Artérias Carótidas/patologia , Adesão Celular/efeitos dos fármacos , Quimiocina CCL5/sangue , Modelos Animais de Doenças , Progressão da Doença , Esquema de Medicação , Fluoxetina/administração & dosagem , Células HEK293 , Células HL-60 , Humanos , Integrina beta1/sangue , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Serotonina/sangue , Inibidores de Captação de Serotonina/administração & dosagem , Transdução de Sinais , Fatores de Tempo
8.
Biochem Biophys Res Commun ; 495(4): 2448-2455, 2018 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-29273504

RESUMO

FGF21, a special member of FGF superfamily, has been proven to have pleiotropic metabolic effects and many potential therapeutic action in various metabolic disorders. Vascular calcification (VC), a perplexing clinical issue, is a major risk factor for many cardiovascular diseases, especially for patients with some metabolic diseases. However, the role of FGF21 on VC in vivo remains unclear. Thus, in this study, we observed the effect and mechanism of FGF21 on VC induced by vitamin D3 plus nicotine (VDN) treated rats. After four weeks' treatment, the calcium overload is mainly manifested in the increased blood pressure, aortic calcium content and ALP activity. Also, the HE and Alizarin-red S staining showed the structural damage of calcified vessel walls. In addition, the level of endogenous FGF21/ß-Klotho/FGFR1 axis was up-regulated in the aortas of VC rats. Furthermore, exogenous FGF21 treatment significantly ameliorated the aortic injury and calcification in VC rats, and the level of ß-Klotho and FGFR1 were furtherly increase. Moreover, FGF21 inhibited the osteogenic transition of VSMCs by down-regulating the expression of bone-associated proteins such as osteopontin (OPN), osteocalcin (OCN) and bone morphogenetic protein-2 (BMP-2), together with restored the expression of SM22α and SM α-actin, which are two of lineage markers in VSMCs. We provide the first evidence that FGF21 can inhibit the development of VC by inhibiting the osteogenic transition of VSMCs in rats. FGF21 might be an efficient endogenous vasoprotective factor for calcification.


Assuntos
Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Fatores de Crescimento de Fibroblastos/metabolismo , Osteogênese , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia , Animais , Doenças da Aorta/induzido quimicamente , Masculino , Nicotina , Ratos , Ratos Sprague-Dawley , Calcificação Vascular/induzido quimicamente , Vitamina D
9.
FASEB J ; 31(11): 4935-4945, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28751527

RESUMO

In utero exposure to diesel exhaust air pollution has been associated with increased adult susceptibility to heart failure in mice, but the mechanisms by which this exposure promotes susceptibility to heart failure are poorly understood. To identify the potential transcriptional effects that mediate this susceptibility, we have performed RNA sequencing analysis on adult hearts from mice that were exposed to diesel exhaust in utero and that have subsequently undergone transverse aortic constriction. We identified 3 target genes, Mir133a-2, Ptprf, and Pamr1, which demonstrate dysregulation after exposure and aortic constriction. Examination of expression patterns in human heart tissues indicates a correlation between expression and heart failure. We subsequently assessed DNA methylation modifications at these candidate loci in neonatal cultured cardiac myocytes after in utero exposure to diesel exhaust and found that the promoter for Mir133a-2 is differentially methylated. These target genes in the heart are the first genes to be identified that likely play an important role in mediating adult sensitivity to heart failure. We have also shown a change in DNA methylation within cardiomyocytes as a result of in utero exposure to diesel exhaust.-Goodson, J. M., Weldy, C. S., MacDonald, J. W., Liu, Y., Bammler, T. K., Chien, W.-M., Chin, M. T. In utero exposure to diesel exhaust particulates is associated with an altered cardiac transcriptional response to transverse aortic constriction and altered DNA methylation.


Assuntos
Doenças da Aorta , Metilação de DNA/efeitos dos fármacos , Exposição Materna/efeitos adversos , Miocárdio/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Transcrição Genética/efeitos dos fármacos , Emissões de Veículos/toxicidade , Animais , Doenças da Aorta/induzido quimicamente , Doenças da Aorta/congênito , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , MicroRNAs/biossíntese , Miocárdio/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/biossíntese , Serina Endopeptidases/biossíntese
10.
J Ethnopharmacol ; 195: 118-126, 2017 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-27880884

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The Angong Niuhuang Pill (ANP) is a well known Chinese traditional therapeutic for the treatment for diseases affecting the Central Nervous System (CNS). Components of the ANP formulation, including Bovis Calculus Sativus, Pulvis Bubali Comus Concentratus, Moschus, Margarita, Cinnabaris, Realgar, Coptidis Rhizoma, Scutellariae Radix, Gardeniae Fructus, Curcumae Radix, and Bomeolum Syntheticum, have been used for the treatment of stroke, encephalitis and emergency meningitis across Asia, especially in China for hundreds of years. OBJECTIVE: The goal of this study was to investigate the anti-atherosclerosis and cardio-protective effects of ANP administration using a rodent model of atherosclerosis induced by a high fat and vitamin D3. METHODS: Specific Pathogen-Free (SPF) 78 male SD rats were randomly divided into a control group and 5 atherosclerotic model groups. The atherosclerotic groups were divided to receive either Simvastatin (SVTT, 0.005g/kg), Low-dose ANP (0.125g/kg), Medium-dose ANP (0.25g/kg), and High-dose ANP (0.5g/kg). Following adaptive feeding for one week, atherosclerosis was induced and the atherosclerosis model was established. Experimental drugs (either simvastatin or ANP) or normal saline were administered intragastrically once daily for 9 weeks starting from the 8th week. A carotid artery ultrasound was performed at the 17th week to determine whether atherosclerosis had been induced. After the atherosclerosis model was successfully established, platelet aggregation rates, serum biochemical indices, apoptosis-related Bcl-2, Bax proteins levels in the heart were assayed. Pathological and histological analysis was completed using artery tissue from different experimental different groups to assess the effects of ANP. RESULTS: ANP significantly decreased aortic membrane thickness, the maximum platelet aggregation rates, and the ratio of low density lipoprotein cholesterol (LDL) to high density lipoprotein cholesterol (HDL). In addition, ANP significantly reduced serum contents of total cholesterol, low density lipoprotein, malondialdehyde, troponin I, high-sensitivity C-reactive protein, and lactate dehydrogenase. ANP markedly improved abnormal pathological conditions of the aorta and heart, and helped to prevent myocardial apoptosis. CONCLUSIONS: We have demonstrated that ANP has robust ant-atherosclerosis and cardio-protective effects on a high-fat and vitamin D3 - induced rodent model of atherosclerosis due to its antiplatelet aggregation, lipid regulatory, antioxidant, anti-inflammatory and anti-apoptotic properties.


Assuntos
Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Doenças das Artérias Carótidas/prevenção & controle , Colecalciferol , Dieta Hiperlipídica , Medicamentos de Ervas Chinesas/farmacologia , Hipolipemiantes/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Aorta Torácica/ultraestrutura , Doenças da Aorta/sangue , Doenças da Aorta/induzido quimicamente , Doenças da Aorta/diagnóstico por imagem , Apoptose/efeitos dos fármacos , Aterosclerose/sangue , Aterosclerose/induzido quimicamente , Aterosclerose/diagnóstico por imagem , Biomarcadores/sangue , Doenças das Artérias Carótidas/sangue , Doenças das Artérias Carótidas/induzido quimicamente , Doenças das Artérias Carótidas/diagnóstico por imagem , Modelos Animais de Doenças , Enzimas/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Mediadores da Inflamação/sangue , Lipídeos/sangue , Masculino , Miocárdio/patologia , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacologia , Ratos Sprague-Dawley , Sinvastatina/farmacologia , Comprimidos , Fatores de Tempo
11.
Arterioscler Thromb Vasc Biol ; 37(1): 53-65, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27834689

RESUMO

OBJECTIVE: Cigarette smoking is an independent risk factor for atherosclerosis. Nicotine, the addictive component of cigarettes, induces mast cell (MC) release and contributes to atherogenesis. The purpose of this study was to determine whether nicotine accelerates atherosclerosis through MC-mediated mechanisms and whether MC stabilizer prevents this pathological process. APPROACH AND RESULTS: Nicotine administration increased the size of atherosclerotic lesions in apolipoprotein E-deficient (Apoe-/-) mice fed a fat-enriched diet. This was accompanied by enhanced intraplaque macrophage content and lipid deposition but reduced collagen and smooth muscle cell contents. MC deficiency in Apoe-/- mice (Apoe-/-KitW-sh/W-sh) diminished nicotine-induced atherosclerosis. Nicotine activated bone marrow-derived MCs in vitro, which was inhibited by a MC stabilizer disodium cromoglycate or a nonselective nicotinic acetylcholine receptor blocker mecamylamine. Further investigation revealed that α7 nicotinic acetylcholine receptor was a target for nicotine activation in MCs. Nicotine did not change atherosclerotic lesion size of Apoe-/-KitW-sh/W-sh mice reconstituted with MCs from Apoe-/-α7nAChR-/- animals. CONCLUSIONS: Activation of α7 nicotinic acetylcholine receptor on MCs is a mechanism by which nicotine enhances atherosclerosis.


Assuntos
Aorta Torácica/efeitos dos fármacos , Doenças da Aorta/induzido quimicamente , Apolipoproteínas E/deficiência , Aterosclerose/induzido quimicamente , Mastócitos/efeitos dos fármacos , Nicotina/toxicidade , Agonistas Nicotínicos/toxicidade , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Animais , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/prevenção & controle , Apolipoproteínas E/genética , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/prevenção & controle , Transplante de Medula Óssea , Degranulação Celular/efeitos dos fármacos , Células Cultivadas , Colesterol/metabolismo , Colágeno/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Progressão da Doença , Células Espumosas/efeitos dos fármacos , Células Espumosas/metabolismo , Predisposição Genética para Doença , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Masculino , Mastócitos/metabolismo , Mastócitos/patologia , Camundongos Knockout , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Antagonistas Nicotínicos/farmacologia , Fenótipo , Placa Aterosclerótica , Proteínas Proto-Oncogênicas c-kit/genética , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Receptor Nicotínico de Acetilcolina alfa7/deficiência , Receptor Nicotínico de Acetilcolina alfa7/genética
12.
Cardiovasc Diabetol ; 15(1): 156, 2016 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-27832775

RESUMO

BACKGROUND: Hyperinsulinemia and insulin resistance have been recently recognized as an important cause of atherosclerosis. Clinical studies have also found that expression of the estrogen receptor is closely related to the incidence of atherosclerosis. This study investigate the effects of insulin and estrogen receptor α (ER-α) in atherosclerosis. METHODS: Double knockout ApoE/Lepr mice were given intraperitoneal injections of insulin, and their aortae were harvested for hematoxylin-eosin staining and immunohistochemical analysis. In addition, vascular smooth muscle cells (VSMCs) were treated with insulin or infected with a lentivirus encoding exogenous ER-α, and changes in gene expression were detected by real-time polymerase chain reaction and western blotting. The methylation levels of the ER-α gene were tested using bisulfite sequencing PCR, and flow cytometry and EdU assay were used to measure VSMCs proliferation. RESULTS: Our results showed that insulin can induce the formation of atherosclerosis. Gene expression analysis revealed that insulin promotes the expression of DNA methyltransferases and inhibits ER-α expression, while 5-aza-2'-deoxycytidine can inhibit this effect of insulin. Bisulfite sequencing PCR analysis showed that methylation of the ER-α second exon region increased in VSMCs treated with insulin. The results also showed that ER-α can inhibit VSMCs proliferation. CONCLUSIONS: Our data suggest that insulin promotes the expression of DNA methyltransferases, induces methylation of ER-α second exon region and decreases the expression of ER-α, thereby interfering with estrogen regulation of VSMCs proliferation, resulting in atherosclerosis.


Assuntos
Doenças da Aorta/metabolismo , Aterosclerose/metabolismo , Metilação de DNA , Receptor alfa de Estrogênio/efeitos dos fármacos , Insulina/toxicidade , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/induzido quimicamente , Doenças da Aorta/genética , Doenças da Aorta/patologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/induzido quimicamente , Aterosclerose/genética , Aterosclerose/patologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Éxons , Feminino , Predisposição Genética para Doença , Camundongos Knockout , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Fenótipo , Ratos , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Fatores de Tempo , Transfecção
13.
J Ethnopharmacol ; 192: 423-430, 2016 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-27620662

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Asian countries, such as China, Japan, and Korea, have witnessed a history of more than 1000 years of Panax notoginseng (Burk.) F.H. Chen's application as a famous traditional medicine for cardiovascular diseases (Zhou et al., 2004). The use of Panax notoginseng (Sanqi) was first recorded in "Bencao Gangmu", which was written by Li Shizhen, a Chinese pharmacologist of the MING dynasty, in 1578. It is included in "The Plant List" as one species of genus Panax (family Araliaceae). Panax notoginseng saponins (PNS) are the major active ingredients extracted from Panax notoginseng. AIM OF THE STUDY: This study investigated whether PNS and the active constituent Ginsenoside Rb1 inhibits adhesion events by regulating the NF-E2-related factor 2 (Nrf2) - p38 - vascular cell adhesion molecule (VCAM)-1 pathway. MATERIALS AND METHODS: The AS model rats were treated once daily with PNS (100mg/kg, i.p.) or Rb1 (40mg/kg, i.p.), and pathological changes in the aortas were observed by electron microscopy and Sudan IV staining. The serum levels of NO, superoxide dismutase (SOD) and TNF-α were measured. Upon treatment with H2O2 to induce oxidative stress, cell viability and LDH levels were measured after cells were cultured with PNS or Rb1. oxidized low density lipoprotein (oxLDL)-induced VCAM-1 and p38 protein expression and THP1 cell adhesion to ECs were assessed after treatment with PNS or Rb1. Nuclear translocation of Nrf2 and expression of its target protein heme oxygenase (HO)-1 were observed in the respective presence of PNS or Rb1. RESULTS: Upon treatment with PNS or Rb1, pathological changes observed in the aortas of AS model rats were alleviated, and an increase in serum levels of NO and SOD and a decrease in TNF-α levels were observed. In vitro treatment with PNS or Rb1 protected endothelial cells (ECs) from H2O2-mediated cytotoxicity, suppressed oxLDL-induced p38 and VCAM-1 protein expression and inhibited THP1 cell adhesion to ECs. Finally, PNS and Rb1 treatment functionally activated Nrf2 in ECs. CONCLUSIONS: Nrf2, an EC protective system, suppresses monocyte adhesion events via the inhibition of the ROS - TNF-α - p38 - VCAM-1 pathway following treatment with PNS, with Rb1 specifically playing an important role among PNS active components.


Assuntos
Aorta/efeitos dos fármacos , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Medicamentos de Ervas Chinesas/farmacologia , Ginsenosídeos/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Panax notoginseng/química , Saponinas/farmacologia , Molécula 1 de Adesão de Célula Vascular/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Aorta/enzimologia , Aorta/ultraestrutura , Doenças da Aorta/induzido quimicamente , Doenças da Aorta/enzimologia , Doenças da Aorta/patologia , Aterosclerose/induzido quimicamente , Aterosclerose/enzimologia , Aterosclerose/patologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Técnicas de Cocultura , Citoproteção/efeitos dos fármacos , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/isolamento & purificação , Ginsenosídeos/isolamento & purificação , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/enzimologia , Masculino , Monócitos/efeitos dos fármacos , Monócitos/enzimologia , Óxido Nítrico/sangue , Fitoterapia , Plantas Medicinais , Ratos Wistar , Saponinas/isolamento & purificação , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/sangue , Fator de Necrose Tumoral alfa/sangue , Zimosan
14.
Mol Cell Biochem ; 419(1-2): 165-76, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27426491

RESUMO

Vascular dysfunction including vascular remodeling and endothelial dysfunction in hypertension often results in poor clinical outcomes and increased risk of vascular accidents. We investigate the effect of treatment with soluble receptor for advanced glycation end products (sRAGE) on vascular dysfunction in spontaneously hypertensive rats (SHR). Firstly, the aortic AGE/RAGE pathway was investigated in SHR. Secondly, SHR received intraperitoneal injections of sRAGE daily for 4 weeks. Effect of sRAGE against vascular dysfunction in SHR and underlying mechanism was investigated. SHR aortas exhibited enhanced activity of aldose reductase, reduced activity of glyoxalase 1, accumulation of methylglyoxal and AGE, and upregulated expression of RAGE. Treatment of SHR with sRAGE had no significant effect on blood pressure, but alleviated aortic hypertrophy and endothelial dysfunction. In vitro, treatment with sRAGE reversed the effect of incubation with AGE on proliferation of smooth muscle cells and endothelial function. Treatment of SHR with sRAGE abated oxidative stress, suppressed inflammation and NF-κB activation, improved the balance between Ang II and Ang-(1-7) through reducing angiotensin-converting enzyme (ACE) activity and enhancing ACE2 expression, and upregulated peroxisome proliferator-activated receptor gamma (PPAR-γ) expression in aortas. In conclusion, treatment with sRAGE alleviated vascular adverse remodeling in SHR, possibly via suppression of oxidative stress and inflammation, improvement in RAS balance, and activation of PPAR-γ pathway.


Assuntos
Aorta/metabolismo , Doenças da Aorta/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Receptor para Produtos Finais de Glicação Avançada , Remodelação Vascular/efeitos dos fármacos , Angiotensina I/metabolismo , Animais , Aorta/patologia , Doenças da Aorta/induzido quimicamente , Doenças da Aorta/patologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Produtos Finais de Glicação Avançada/metabolismo , Lactoilglutationa Liase/metabolismo , NF-kappa B/metabolismo , PPAR gama/metabolismo , Fragmentos de Peptídeos/metabolismo , Peptidil Dipeptidase A/biossíntese , Ratos , Ratos Endogâmicos SHR , Espécies Reativas de Oxigênio/metabolismo
15.
Arterioscler Thromb Vasc Biol ; 36(8): 1577-86, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27339459

RESUMO

OBJECTIVE: A solid body of evidence supports a role of extracellular ATP and its P2 receptors in innate and adaptive immunity. It promotes inflammation as a danger signal in various chronic inflammatory diseases. Thus, we hypothesize contribution of extracellular ATP and its receptor P2Y2 in vascular inflammation and atherosclerosis. APPROACH AND RESULTS: Extracellular ATP induced leukocyte rolling, adhesion, and migration in vivo as assessed by intravital microscopy and in sterile peritonitis. To test the role of extracellular ATP in atherosclerosis, ATP or saline as control was injected intraperitoneally 3× a week in low-density lipoprotein receptor(-/-) mice consuming high cholesterol diet. Atherosclerosis significantly increased after 16 weeks in ATP-treated mice (n=13; control group, 0.26 mm2; ATP group, 0.33 mm2; P=0.01). To gain into the role of ATP-receptor P2Y2 in ATP-induced leukocyte recruitment, ATP was administered systemically in P2Y2-deficient or P2Y2-competent mice. In P2Y2-deficient mice, the ATP-induced leukocyte adhesion was significantly reduced as assessed by intravital microscopy. P2Y2 expression in atherosclerosis was measured by real-time polymerase chain reaction and immunohistochemistry and demonstrates an increased expression mainly caused by influx of P2Y2-expressing macrophages. To investigate the functional role of P2Y2 in atherogenesis, P2Y2-deficient low-density lipoprotein receptor(-/-) mice consumed high cholesterol diet. After 16 weeks, P2Y2-deficient mice showed significantly reduced atherosclerotic lesions with decreased macrophages compared with P2Y2-competent mice (n=11; aortic arch: control group, 0.25 mm(2); P2Y2-deficient, 0.14 mm2; P=0.04). Mechanistically, atherosclerotic lesions from P2Y2-deficient mice expressed less vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 RNA. CONCLUSIONS: We show that extracellular ATP induces vascular inflammation and atherosclerosis via activation of P2Y2.


Assuntos
Trifosfato de Adenosina/toxicidade , Aorta/efeitos dos fármacos , Doenças da Aorta/induzido quimicamente , Aterosclerose/induzido quimicamente , Inflamação/induzido quimicamente , Receptores Purinérgicos P2Y2/efeitos dos fármacos , Trifosfato de Adenosina/administração & dosagem , Trifosfato de Adenosina/sangue , Animais , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Dieta Hiperlipídica , Modelos Animais de Doenças , Genótipo , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Injeções Intraperitoneais , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Migração e Rolagem de Leucócitos/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Peritonite/genética , Peritonite/metabolismo , Fenótipo , Placa Aterosclerótica , Receptores de LDL/deficiência , Receptores de LDL/genética , Receptores Purinérgicos P2Y2/deficiência , Receptores Purinérgicos P2Y2/genética , Receptores Purinérgicos P2Y2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo
16.
J Ethnopharmacol ; 191: 245-253, 2016 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-27340105

RESUMO

The total flavonoids from Persimmon leaves (PLF), extracted from the leaves of Diospyros kaki L. Dispryosl and Ebenaceae, is reported to possess many beneficial health effects. However, the oral bioavailability of PLF is relatively low due to its poor solubility. In the present study, the phospholipid complexes of total flavonoids from Persimmon leaves (PLF-PC) was prepared to enhance the oral bioavailability of PLF and to evaluate its antiatherosclerotic properties in atherosclerosis rats in comparison to PLF. A HPLC-MS method was developed and validated for the determination of quercetin and kaempferol in rats plasma to assess the oral bioavailability of PLF-PC. The effect of PLF (50mg/kg/d) and PLF-PC (equivalent to PLF 50mg/kg/d) on atherosclerosis rats induced by excessive administration of vitamin D (600,000IU/kg) and cholesterol (0.5g/kg/d) was assessed after orally administered for 4 weeks. The relative bioavailabilities of quercetin and kaempferol in PLF-PC relative to PLF were 242% and 337%, respectively. The levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), apolipoprotein A1 (ApoA1) and apolipoprotein B (ApoB) in serum were measured by an automatic biochemistry analyzer. The morphological changes of aorta were observed with optical microscopy. According to the levels of biochemical parameters in serum and the morphological changes of aorta, PLF-PC showed better therapeutic efficacy compared to PLF. Thus, PLF-PC holds a promising potential for increasing the oral bioavailability of PLF. Moreover, PLF-PC exerts better therapeutic potential in the treatment of atherosclerotic disease than PLF.


Assuntos
Aorta/efeitos dos fármacos , Doenças da Aorta/tratamento farmacológico , Aterosclerose/tratamento farmacológico , Diospyros/química , Flavonoides/farmacologia , Hipolipemiantes/farmacologia , Lipídeos/sangue , Fosfolipídeos/farmacologia , Extratos Vegetais/farmacologia , Administração Oral , Animais , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/sangue , Doenças da Aorta/induzido quimicamente , Doenças da Aorta/patologia , Aterosclerose/sangue , Aterosclerose/induzido quimicamente , Aterosclerose/patologia , Disponibilidade Biológica , Biomarcadores/sangue , Cromatografia Líquida , Modelos Animais de Doenças , Composição de Medicamentos , Flavonoides/administração & dosagem , Flavonoides/isolamento & purificação , Flavonoides/farmacocinética , Hipolipemiantes/administração & dosagem , Hipolipemiantes/isolamento & purificação , Hipolipemiantes/farmacocinética , Masculino , Espectrometria de Massas , Fosfolipídeos/administração & dosagem , Fosfolipídeos/farmacocinética , Fitoterapia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacocinética , Folhas de Planta/química , Plantas Medicinais , Placa Aterosclerótica , Ratos Sprague-Dawley , Vitamina D
17.
Kyobu Geka ; 69(2): 112-5, 2016 Feb.
Artigo em Japonês | MEDLINE | ID: mdl-27075151

RESUMO

A 62-year-old female complained of easy fatigue and sore throat and chest computed tomography revealed acute type A aortic dissection with pericardial effusion and chronic type B aortic dissection that was on set in 2012.She had past history of systemic lupus erythematosus (SLE) 23 years ago and received steroid therapy since then. Blood examination showed inflammation reaction and slight disseminated intravascular coagulopathy. We underwent 2 stage operation safely. In 1st stage we performed ascending graft replacement to type A aortic dissection and in 2nd stage we carried out thoracic endovascular arterial replacement to type B aortic dissection. She had no complication like cerebral infarction and paraplegia postoperatively. It seemed to be rare for the patient in SLE complicated with acute type A and chronic type B aortic dissection and the cause of double aortic dissection was considered long steroid therapy. We carried out 2 stage operation by conventional surgery and endovascular treatment safely without any postoperative complication. We need medical follow up continuously to residual aneurysm.


Assuntos
Aneurisma Dissecante/cirurgia , Doenças da Aorta/cirurgia , Lúpus Eritematoso Sistêmico/complicações , Doença Aguda , Aneurisma Dissecante/induzido quimicamente , Doenças da Aorta/induzido quimicamente , Doença Crônica , Feminino , Humanos , Pessoa de Meia-Idade , Esteroides/efeitos adversos , Esteroides/uso terapêutico , Tomografia Computadorizada por Raios X
18.
J Am Heart Assoc ; 5(2)2016 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-26908406

RESUMO

BACKGROUND: Treatment of prostate cancer often involves androgen deprivation therapy (ADT) by gonadotropin-releasing hormone (GnRH) receptor agonists, GnRH receptor antagonists, or orchiectomy. ADT may increase the rate of cardiovascular disease events, but recent clinical studies suggested that not all means of ADT carry the same risk, raising the possibility of non-testosterone-mediated effects of different forms of ADT on atherosclerosis. Here we compared effects of ADT on atherosclerosis in intact and orchiectomized Apoe-deficient mice. METHODS AND RESULTS: Chow-fed Apoe-deficient mice were allocated to orchiectomy and/or monthly injections with the GnRH receptor agonist leuprolide or the GnRH receptor antagonist degarelix. Atherosclerosis was quantified at 26 weeks of age in the aortic arch by en face examination and in the aortic root by histology. In intact Apoe-deficient mice, all types of ADT reduced testosterone production to castration levels. Although hypercholesterolemia was accentuated in leuprolide-treated mice, the amount and composition of atherosclerosis was not different between the different types of ADT. In orchiectomized Apoe-deficient mice, leuprolide, but not degarelix, augmented hypercholesterolemia, changed body, thymus, and spleen weights, and increased atherosclerosis in the aortic root. No direct effects of the drugs were detectable on cytokine secretion from murine bone marrow-derived macrophages or on splenocyte proliferation. CONCLUSIONS: No differences in the development of atherosclerosis were detected among groups of intact Apoe-deficient mice treated with different types of ADT. A pro-atherogenic, possibly cholesterol-mediated, effect of leuprolide was seen in orchiectomized mice that might be relevant for understanding the potential cardiovascular risk associated with GnRH agonist-based ADT.


Assuntos
Antagonistas de Androgênios/toxicidade , Aorta/efeitos dos fármacos , Doenças da Aorta/induzido quimicamente , Aterosclerose/induzido quimicamente , Hipercolesterolemia/induzido quimicamente , Leuprolida/toxicidade , Oligopeptídeos/toxicidade , Orquiectomia , Animais , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Células Cultivadas , Modelos Animais de Doenças , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fatores de Risco , Fatores de Tempo
19.
Arterioscler Thromb Vasc Biol ; 36(3): 456-65, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26821944

RESUMO

OBJECTIVE: T cell immunoglobulin and mucin domain (Tim) proteins are expressed by numerous immune cells, recognize phosphatidylserine on apoptotic cells, and function as costimulators or coinhibitors. Tim-1 is expressed by activated T cells but is also found on dendritic cells and B cells. Tim-4, present on macrophages and dendritic cells, plays a critical role in apoptotic cell clearance, regulates the number of phosphatidylserine-expressing activated T cells, and is genetically associated with low low-density lipoprotein and triglyceride levels. Because these functions of Tim-1 and Tim-4 could affect atherosclerosis, their modulation has potential therapeutic value in cardiovascular disease. APPROACH AND RESULTS: ldlr(-/-) mice were fed a high-fat diet for 4 weeks while being treated with control (rat immunoglobulin G1) or anti-Tim-1 (3D10) or -Tim-4 (21H12) monoclonal antibodies that block phosphatidylserine recognition and phagocytosis. Both anti-Tim-1 and anti-Tim-4 treatments enhanced atherosclerosis by 45% compared with controls by impairment of efferocytosis and increasing aortic CD4(+)T cells. Consistently, anti-Tim-4-treated mice showed increased percentages of activated T cells and late apoptotic cells in the circulation. Moreover, in vitro blockade of Tim-4 inhibited efferocytosis of oxidized low-density lipoprotein-induced apoptotic macrophages. Although anti-Tim-4 treatment increased T helper cell (Th)1 and Th2 responses, anti-Tim-1 induced Th2 responses but dramatically reduced the percentage of regulatory T cells. Finally, combined blockade of Tim-1 and Tim-4 increased atherosclerotic lesion size by 59%. CONCLUSIONS: Blockade of Tim-4 aggravates atherosclerosis likely by prevention of phagocytosis of phosphatidylserine-expressing apoptotic cells and activated T cells by Tim-4-expressing cells, whereas Tim-1-associated effects on atherosclerosis are related to changes in Th1/Th2 balance and reduced circulating regulatory T cells.


Assuntos
Anticorpos Monoclonais/toxicidade , Doenças da Aorta/induzido quimicamente , Aterosclerose/induzido quimicamente , Linfócitos T CD4-Positivos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Proteínas de Membrana/antagonistas & inibidores , Receptores de LDL/deficiência , Animais , Doenças da Aorta/genética , Doenças da Aorta/imunologia , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Apoptose/efeitos dos fármacos , Aterosclerose/genética , Aterosclerose/imunologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Dieta Hiperlipídica , Modelos Animais de Doenças , Feminino , Receptor Celular 1 do Vírus da Hepatite A , Lipoproteínas LDL/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Camundongos Knockout , Fagocitose/efeitos dos fármacos , Placa Aterosclerótica , Receptores de LDL/genética , Transdução de Sinais/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia
20.
Ann Thorac Cardiovasc Surg ; 22(5): 318-321, 2016 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-26780951

RESUMO

A 77-year-old woman underwent emergency ascending aortic replacement for type A acute aortic dissection. Fifteen days after the operation, she had motor and sensory disturbances in the lower limbs. Computed tomography revealed multiple aortic thrombi and disrupted blood flow in the right external iliac and left common iliac arteries. She underwent an emergency thrombectomy for acute limb ischemia. Because heparin-induced-thrombocytopenia (HIT) was suspected to have caused the multiple aortic thrombi, we postoperatively changed the anticoagulant therapy from heparin to argatroban. Seventeen days after the first operation, gastrointestinal bleeding developed, and the patient died of mesenteric ischemia caused by HIT. Arterial embolization caused by HIT after cardiovascular surgery is a rare, but fatal event. To avoid fatal complications, early diagnosis and early treatment are essential. Use of a scoring system would probably facilitate early diagnosis.


Assuntos
Aneurisma Dissecante/cirurgia , Anticoagulantes/efeitos adversos , Aneurisma Aórtico/cirurgia , Doenças da Aorta/induzido quimicamente , Implante de Prótese Vascular , Heparina/efeitos adversos , Trombocitopenia/induzido quimicamente , Trombose/induzido quimicamente , Doença Aguda , Idoso , Aneurisma Dissecante/diagnóstico por imagem , Anticoagulantes/administração & dosagem , Aneurisma Aórtico/diagnóstico por imagem , Doenças da Aorta/diagnóstico por imagem , Aortografia/métodos , Angiografia por Tomografia Computadorizada , Substituição de Medicamentos , Emergências , Evolução Fatal , Feminino , Hemorragia Gastrointestinal/etiologia , Humanos , Isquemia Mesentérica/etiologia , Ácidos Pipecólicos/administração & dosagem , Trombocitopenia/diagnóstico por imagem , Trombose/diagnóstico por imagem , Fatores de Tempo , Resultado do Tratamento
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