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1.
Eur Rev Med Pharmacol Sci ; 20(10): 2174-82, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27249621

RESUMO

OBJECTIVE: Although vitamin C is a strong antioxidant, the epidemiologic evidence to support its role in lowering risk of cardiovascular disease is inconsistent. In order to define the role of vitamin C in vascular pathophysiology, we have investigated the effect of vitamin C on the tissue factor (TF) and Factor VII Activating Protease (FSAP) expression induced by lipopolysaccharide (LPS) in human monocyte-derived macrophages. MATERIALS AND METHODS: Vitamin C at clinically relevant doses was tested to its ability to influence the LPS- and reactive oxygen species (ROS) - generating system of xanthine/xanthine oxidase (X/XO) NF-kB activity in human monocyte-derived macrophages. RESULTS: Vitamin C-treatment prevents LPS- and ROS-induced DNA-binding activity of NF-kB in a concentration-dependent fashion. Vitamin C also inhibited the phosphorylation and proteolytic degradation of the inhibitor protein IkBa. In parallel to regulate NF-kB activity, vitamin C reduced the expression of TF and FSAP, genes known to be induced by bacterial LPS and triggered the extrinsic coagulation cascade and linked thrombosis with inflammation. CONCLUSIONS: Vitamin C alters pro-inflammatory and pro-coagulatory processes via inhibition of NF-kB activation and exerts beneficial antiatherogenic effects on human monocyte-derived macrophages in addition to its anti-oxidant properties.


Assuntos
Ácido Ascórbico/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Humanos , Lipopolissacarídeos/farmacologia , Macrófagos/fisiologia , NF-kappa B/metabolismo , Serina Endopeptidases/metabolismo , Tromboplastina/metabolismo
2.
Thorac Cardiovasc Surg ; 57(7): 386-90, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19795323

RESUMO

OBJECTIVE: Inflammation plays a major role in the pathogenesis of coronary artery disease (CAD) and myocardial infarction (MI). CD14 is the receptor for bacterial lipopolysaccharide in monocytes and mediates the production of proinflammatory cytokines. The promoter of the CD14 gene has a polymorphic site in position - 159 (C-->T) and T-homozygotes have been shown to express higher amounts of CD14 by some investigators. We and others have found an association of the T-allele with past MI in former studies, but reports in the literature are contradictory. METHODS AND RESULTS: We investigated a study group with an assumed high genetic risk by selecting 200 patients suffering from angiographically verified CAD or MI who were younger than 50 years or who had only one or no risk factor (hypertension, smoking, elevated body mass index, impaired glucose tolerance or elevated cholesterol levels). We used 252 healthy subjects as controls. Additionally, the levels of soluble (s) CD14 in plasma and amount of membranous (m) CD14 on the surface of monocytes were determined in different genotypes. We found no association of either genotype with CAD, extent of CAD, or a history of MI. No significant correlation was found after adjustment for vascular risk factors. In addition, no significant differences in the density of monocyte mCD14 or in plasma levels of sCD14 were detectable among the various genotypes. CONCLUSIONS: The assumed weak association of the TT-genotype of the CD14 promoter polymorphism with MI could not be not established in a well-defined group of young patients with a high genetic risk. The association of the polymorphism with expression of sCD14 or mCD14 was not confirmed.


Assuntos
Doença da Artéria Coronariana/genética , Receptores de Lipopolissacarídeos/genética , Infarto do Miocárdio/genética , Polimorfismo Genético , Regiões Promotoras Genéticas , Adulto , Estudos de Casos e Controles , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/imunologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Receptores de Lipopolissacarídeos/sangue , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/imunologia , Razão de Chances , Fenótipo , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença
3.
Transplant Proc ; 41(6): 2628-30, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19715989

RESUMO

BACKGROUND: In the initial phase after cardiac transplantation, mononuclear cells infiltrate the graft initiating a relevant impulse for rejection. 3-Deazaadenosin (c3Ado), an analog of adenosine, has demonstrated in vitro anti-inflammatory properties. Furthermore, in vivo studies on arteriosclerosis development and septic myocardial dysfunction c3Ado revealed reduced cellular infiltration. In addition ischemia and reperfusion injury could be diminished in a pulmonary animal model. The aim of our study was to investigate the properties of c3Ado to reduce adhesion molecule expression and cellular infiltration in a fully allogeneic cardiac transplant model. METHODS AND RESULTS: Lewis rats were challenged with Wistar-Furth cardiac allografts. Untreated grafts were rejected within 7 days (group 1). In group 2, animals received 2 x 5 mg c3Ado SC per day. Grafts were harvested on days 1, 3, and 6 after transplantation for further examination (n = 4 per group and time point). Immunohistochemical examination revealed significant reduction of graft-infiltrating MHC II positive cells, T-cell receptor positive cells (R73), as well as ED1-positive monocytes and macrophages (P < .01) at days 3 and 6 after transplantation. Adhesion molecule (ICAM-1, VCAM-1) expression on days 1 and 3 after transplantation was almost completely diminished in c3Ado-treated grafts. CONCLUSION: Thus, c3Ado is able to reduce graft infiltration by preventing leukocyte evasion through the suppression of adhesion molecule expression. This may be a novel strategy to protect transplanted organs from early damage after transplantation and extend organ survival after transplantation.


Assuntos
Anti-Inflamatórios/uso terapêutico , Rejeição de Enxerto/prevenção & controle , Transplante de Coração/imunologia , Leucócitos/fisiologia , Tubercidina/uso terapêutico , Animais , Modelos Animais de Doenças , Transplante de Coração/patologia , Antígenos de Histocompatibilidade Classe II/efeitos dos fármacos , Antígenos de Histocompatibilidade Classe II/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Leucócitos/efeitos dos fármacos , Masculino , Ratos , Ratos Endogâmicos Lew , Ratos Endogâmicos WF , Transplante Homólogo/imunologia , Transplante Homólogo/patologia , Molécula 1 de Adesão de Célula Vascular/metabolismo
6.
Hamostaseologie ; 27(5): 319-25; quiz 326-7, 2007 Dec.
Artigo em Alemão | MEDLINE | ID: mdl-18060240

RESUMO

Recent advances in the diagnosis and the treatment of acute coronary syndromes (ACS) have led to a substantial reduction of major coronary events, to an improvement in patient outcome and the definition of new guidelines. Current strategies for the treatment of patients with non-ST-elevation ACS recommend a combined antithrombotic therapy (including aspirin, clopidogrel, anticoagulation with low-molecular weight or unfractionated heparins or FXa-inhibitors or direct antithrombins and, eventually glycoprotein IIb/IIIa receptor antagonists). This combined antithrombotic therapy allows to increase the benefit of an early invasive strategy including coronary angiogram with stent percutaneous coronary angioplasty. The purpose of this review is to discuss and highlight the recommendations for the appropriate use of antithrombotic strategies in the setting of angioplasty in ACS patients.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Fibrinolíticos/uso terapêutico , Terapia Trombolítica/métodos , Anticoagulantes/uso terapêutico , Quimioterapia Combinada , Heparina/uso terapêutico , Humanos
7.
Am J Transplant ; 7(4): 789-98, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17391124

RESUMO

Sanglifehrin A (SFA) is a novel compound with unsurpassed cyclophilin-binding affinity, but relatively low direct antilymphocytic activity. Here, we report the capacity of SFA to selectively inhibit key dendritic cell (DC) functions in vivo and to suppress acute and chronic heart allograft rejection. We show that in vivo, SFA profoundly decreases DC receptor-mediated endocytosis and macropinocytosis and DC-T-cell allostimulatory activity. Furthermore, SFA abrogates >90% of IL-12p70 production in vivo while having no significant effect on IL-10 and TNF-alpha production. In a rat vascularized heart transplant model, SFA alone did not prevent graft rejection and rejection occurred within 23 days after low-dose CsA, whereas addition of SFA to low-dose CsA promoted long-term graft survival (median survival time >100 days; p = 0.0007). With respect to chronic rejection, SFA + CsA almost completely prevented graft arteriosclerosis compared to animals treated with CsA alone and controls. We propose that SFA represents a novel class of immunophilin-binding immunosuppressants with high activity against DCs and the development of graft vasculopathy in CsA-treated recipients.


Assuntos
Ciclosporina/uso terapêutico , Células Dendríticas/imunologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/fisiologia , Transplante de Coração/imunologia , Transferência Adotiva , Animais , Antígenos de Superfície/análise , Células Dendríticas/efeitos dos fármacos , Sobrevivência de Enxerto/imunologia , Imunossupressores/uso terapêutico , Lactonas/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Modelos Animais , Ratos , Ratos Endogâmicos Lew , Ratos Endogâmicos WF , Compostos de Espiro/uso terapêutico , Transplante Homólogo
8.
Hamostaseologie ; 26(2): 99-103, 2006 May.
Artigo em Alemão | MEDLINE | ID: mdl-16676050

RESUMO

This article reviews the current understanding of the pathophysiology of acute coronary syndrome and how these concepts have altered our clinical approach to the acute phase of coronary heart disease. Thrombosis due to erosion or, in most cases, rupture of a vulnerable atherosclerotic plaque underlies most acute coronary syndromes. The protective fibrous cap undergoes degradative processes controlled by inflammatory mediators that break down the interstitial collagen within the fibrous cap. Thrombus formation depends on factors in the solid-phase of the ruptured plaque as well as on fluid-phase determinants in blood. Depending on the degree of thrombus formation the subsequent obstruction of the coronary artery is followed clinically by unstable angina, non-ST- and ST-segment elevation myocardial infarction.


Assuntos
Doença das Coronárias/fisiopatologia , Doença Aguda , Doença das Coronárias/classificação , Doença das Coronárias/diagnóstico , Doença das Coronárias/epidemiologia , Humanos , Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/epidemiologia , Isquemia Miocárdica/fisiopatologia , Prognóstico , Síndrome
9.
Hamostaseologie ; 26(2): 106-13, 2006 May.
Artigo em Alemão | MEDLINE | ID: mdl-16676052

RESUMO

Non-ST segment elevation myocardial infarction (NSTEMI) is an acute life-threatening event which has a high rate of recurrence. Combined antithrombotic therapy (including cacetylsalicylic acid, clopidogrel, heparins and glycoprotein IIb/IIIa receptor antagonists) substantially reduced major coronary events during the acute phase of coronary heart disease with a good tolerance because of the short duration of such aggressive strategy. The combined antithrombotic strategy also allows to increase the benefit of an early invasive strategy including coronary angiogram with stent percutaneous coronary angioplasty which recent trials have shown that to be preferable to a conservative approach in these high risk patients. Antithrombotic and antiplatelet therapy in association with coronary revascularization play an important role in the prevention of an adverse outcome. Recently, clopidogrel has been shown reduce recurrent ischaemic events, both early and during the first year after non-ST-segment elevation myocardial infarction. An ideal antithrombotic and antiplatelet strategy will reduce events before revascularization, enhance the revascularization procedure without excessive bleeding.


Assuntos
Angina Instável/tratamento farmacológico , Antitrombinas/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/fisiopatologia , Anticoagulantes/uso terapêutico , Heparina/uso terapêutico , Humanos , Infarto do Miocárdio/classificação , Inibidores da Agregação Plaquetária/uso terapêutico , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores
11.
Hamostaseologie ; 25(1): 6-12, 2005 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-15711714

RESUMO

Recent advances in the diagnosis and the treatment of acute coronary syndromes (ACS) have led to a substantial reduction of major coronary events, to an improvement in patient outcome, and to the definition of new guidelines. Current strategies for the treatment of patients with non-ST-elevation ACS recommend a combined antithrombotic therapy (including acetyl salicylic acid, clopidogrel, low-molecular weight or unfractionated heparins and, eventually glycoprotein IIb/IIIa receptor antagonists). This combined antithrombotic therapy allows to increase the benefit of an early invasive strategy including coronary angiogram with stent percutaneous coronary angioplasty. The purpose of this review is to discuss and highlight the actual recommendations for the appropriate use of antithrombotic strategies for ACS patients.


Assuntos
Doença das Coronárias/tratamento farmacológico , Fibrinolíticos/uso terapêutico , Terapia Trombolítica/métodos , Ticlopidina/análogos & derivados , Doença Aguda , Aspirina/uso terapêutico , Clopidogrel , Quimioterapia Combinada , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Ticlopidina/uso terapêutico
12.
Z Kardiol ; 93(1): 63-8, 2004 Jan.
Artigo em Alemão | MEDLINE | ID: mdl-14740243

RESUMO

A 73-year-old obese woman underwent coronary artery-bypass operation in 11/1995 because of a coronary two vessel disease. The left coronary artery was bypassed by the left mammarial internal artery. In 2 and 3/2002, balloon-dilatation of stenoses of the right coronary artery and the circumflex was performed. Angina pectoris relapsed and in 9/2002 the patient was admitted to our hospital with tentative diagnosis of restenosis. Physical investigation showed a blood pressure of the right arm of 160/80 and of the left arm of 120/ 80 mmHg. Coronarography showed the three vessel disease known since 2/2002 with a restenosis of the right coronary artery which was immediately treated by balloon-dilatation and stent-implantation. Colour duplex-sonography of the carotid and subclavian arteries revealed extraordinary plaques and a reduced flow of the left vertebral artery. The left subclavian artery could only be seen distal to the discharge of the vertebral artery and showed a poststenotic flow. The patient had angina pectoris when carrying out personal hygiene already 2 days after balloon-dilatation and stent-implantation. ECG showed new aspects. Coronarography showed no relapse of stenosis, but 70% stenosis of the left subclavian artery with a marked coronary-steal-syndrome. In 10/ 2002, the patient underwent balloon-dilatation and stent-implantation of the subclavian stenosis and became free of complaints. Coronary-steal-syndrome can be the reason for persistent angina pectoris in spite of successful coronary artery-bypass operation with a mammarial internal bypass. It is absolutely necessary to take blood pressure from both arms to recognise a possible stenosis of the subclavian artery which can be the key to all.


Assuntos
Angina Pectoris/diagnóstico , Angioplastia Coronária com Balão , Doença das Coronárias/cirurgia , Reestenose Coronária/diagnóstico , Revascularização Miocárdica , Complicações Pós-Operatórias/diagnóstico , Stents , Síndrome do Roubo Subclávio/diagnóstico , Idoso , Angina Pectoris/terapia , Angioplastia com Balão , Reestenose Coronária/terapia , Diagnóstico Diferencial , Feminino , Humanos , Complicações Pós-Operatórias/terapia , Retratamento , Síndrome do Roubo Subclávio/terapia
13.
Int J Clin Pharmacol Ther ; 41(9): 397-401, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-14518599

RESUMO

OBJECTIVE: The benefits of statin therapy in cardiovascular medicine are ascribed to its lipid-lowering effect as well as its anti-inflammatory properties. Whereas all statins have been shown to reduce cholesterol plasma levels, their effect on inflammatory markers has been inconsistent. Here, we show that statins differ markedly in their effectiveness in preventing activation of NF-kappaB, a transcription factor involved in the activation of immediately early genes during inflammation. METHODS: Six statins (atorvastatin (Atv), cerivastatin (Cer), fluvastatin (Flu), lovastatin (Lov), pravastatin (Pra), simvastatin (Sim)) were tested for their ability to influence the induction of NF-kappaB in human monocytes (Mo) during inflammation. Mo isolated from healthy blood donors were incubated with LPS (10 microg/ml) in the presence and absence of statin (0.001-5 microM). NF-kappaB binding activity (EMSA), degradation and phosphorylation of the inhibitor protein IkappaB-alpha (Western blotting), tissue factor (TF) mRNA (rtPCR), and TF activity (clotting assay) were analyzed. RESULTS: All statins inhibited LPS-induced NF-kappaB binding activity in Mo in a dose-dependent manner. The inhibitory effect was due to reduced phosphorylation and degradation of the NF-kappaB inhibitor protein IkappaB, and was primarily dependent on the absence of mevalonate. Whilst this effect appeared with all statins, there were marked differences in the degree of inhibition between the statins. Cer (45 +/- 9% inhibition, p < 0.05) was 9-fold more effective in reducing NF-kappaB activation than Flu (5 +/- 10% inhibition). The differences in the potency of statins (Cer > Atv > Sim > Pra > Lov > Flu) were also reflected at the transcriptional level and the protein level of NF-kappaB controlled tissue factor expression. CONCLUSIONS: The finding that statins differ in their potency in interfering with the activation of NF-kappaB signaling in human monocytes further supports the hypothesis that some statins inhibit the inflammatory response more than others.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Monócitos/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Proteínas I-kappa B/metabolismo , Monócitos/metabolismo , Inibidor de NF-kappaB alfa , NF-kappa B/biossíntese , NF-kappa B/genética , Fosforilação , Reação em Cadeia da Polimerase , RNA Mensageiro/biossíntese , RNA Mensageiro/metabolismo , Tromboplastina/genética , Tromboplastina/metabolismo
14.
J Immunol ; 166(12): 7112-20, 2001 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-11390456

RESUMO

Tissue factor (TF), the primary initiator of blood coagulation with structural homology to the cytokine receptor family, has been implicated in various vascular processes including metastasis, angiogenesis, and atherosclerosis. Within the vasculature, monocytes and endothelial cells (EC) can be activated to synthesize TF depending on the induction of NF-kappaB. Despite the undisputed value of cyclosporin A (CsA) as an immunosuppressant, problems have emerged due to induction of vascular changes by a poorly understood mechanism. We demonstrate that CsA has opposite effects on TF gene expression, inhibiting NF-kappaB-mediated TF gene transcription in monocytes but enhancing it in EC. To test whether CsA binding proteins (cyclophilins) can mediate these CsA effects we used a nonimmunosuppressant analog of CsA that binds to cyclophilins but does not inhibit the Ca2+/calmodulin-dependent phosphatase calcineurin (Cn). This drug lacked regulatory function for NF-kappaB and TF expression suggesting that Cn is responsible for the inverse gene regulation. The key function of Cn was supported by experiments demonstrating that other phosphatase inhibitors also either positively or negatively regulated NF-kappaB in monocytes and EC. Calcineurin was demonstrated to regulate NF-kappaB activation at the level of IkappaBalpha degradation, because agonist-induced phosphorylation and subsequent degradation of IkappaBalpha is prevented by Cn inhibitors in monocytes but enhanced in EC. These data identify Cn as an opposite regulator in generating transcriptionally active NF-kappaB, and they confirm the presumption that the ability of Cn to participate in NF-kappaB transactivation is not T cell specific.


Assuntos
Calcineurina/fisiologia , Endotélio Vascular/metabolismo , Monócitos/metabolismo , Tromboplastina/antagonistas & inibidores , Tromboplastina/biossíntese , Inibidores de Calcineurina , Células Cultivadas , Ciclosporina/farmacologia , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/enzimologia , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Monócitos/efeitos dos fármacos , Monócitos/enzimologia , Peptidilprolil Isomerase/metabolismo , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/biossíntese , Tromboplastina/genética , Ativação Transcricional/efeitos dos fármacos , Veias Umbilicais
15.
Med Klin (Munich) ; 95(9): 517-22, 2000 Sep 15.
Artigo em Alemão | MEDLINE | ID: mdl-11028168

RESUMO

HISTORY: A 65-year-old woman had suffered from relapsing ventricular tachycardias (VT) since 1996. FINDINGS: Physical examination was normal. An arrhythmogenic substrate was found in the right ventricular outflow tract by electrophysiological examination. Nuclear magnetic resonance imaging (MRI) showed an infiltration of the right heart. Myocardial biopsy revealed a high-grade centroblastic non Hodgkin lymphoma. The patient was now transferred to our hospital for further treatment. Lactate dehydrogenase was elevated (2,030 U/l). Echocardiography showed a thickened and more reflecting right ventricular myocardium. Bone marrow aspiration and MRI/computed tomography of abdomen and thorax excluded a generalized stage. Ventricular tachycardias were caused by a primary cardiac lymphoma. TREATMENT AND COURSE: Combined radio-chemotherapy succeeded in complete remission. High-frequency ablation and amiodarone failed. Although MRI showed no more vital lymphoma after the combined radio-chemotherapy the patient suffered from spontaneous and symptomatic relapses of VT. Therefore this patient with primary cardiac lymphoma was the first in literature to get a defibrillator (ICD). The incidence of VT decreased and up to now the patient showed no relapse of the non Hodgkin lymphoma (follow-up 23 months).


Assuntos
Neoplasias Cardíacas/diagnóstico , Linfoma não Hodgkin/diagnóstico , Miocárdio/patologia , Taquicardia/terapia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Desfibriladores Implantáveis , Diagnóstico Diferencial , Eletrocardiografia , Feminino , Neoplasias Cardíacas/complicações , Neoplasias Cardíacas/tratamento farmacológico , Neoplasias Cardíacas/patologia , Humanos , Linfoma não Hodgkin/complicações , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/patologia , Taquicardia/etiologia , Resultado do Tratamento
16.
Circulation ; 102(3): 357-63, 2000 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-10899102

RESUMO

BACKGROUND-Intravascular clotting has been implicated in the pathogenesis of cardiac allograft vasculopathy (CAV). We previously identified the expression of tissue factor (TF), the primary cellular initiator of blood coagulation, within the coronary intima, which was associated with neointimal thickening. In the present study, the effect of recombinant hirudin on CAV was assessed in Lewis to Fisher rat heterotopic cardiac allografts. METHODS AND RESULTS-Transplant recipients were randomized to a control group (n=10) and a hirudin-treated group (n=12; 2 mg. kg(-1). d(-1) SC). Histological evaluations of rejection, CAV, and TF staining were performed 120 days after transplantation. No significant differences were observed between the 2 groups with respect to the degree of rejection. Hirudin significantly (P<0.05) suppressed the development of CAV in the graft microvessels, but it was less effective in large coronary arteries. Graft intimal cells, isolated by laser-assisted cell picking, showed a marked upregulation of TF gene transcription, which was prevented by hirudin (P<0.01). As demonstrated by immunohistochemistry and quantitative analyses of TF mRNA levels by real-time polymerase chain reaction, hirudin treatment resulted in a significant reduction of TF protein and mRNA expression (P<0.001). CONCLUSIONS-Treatment with hirudin in this rat cardiac transplant model inhibited TF expression and decreased neointimal hyperplasia. These results suggest that TF inhibition by hirudin, in addition to its direct effect on thrombin, may attenuate the hypercoagulable state and prevent the development of CAV at least in restricted sites of the graft coronary vasculature.


Assuntos
Doença da Artéria Coronariana/patologia , Transplante de Coração , Hirudinas/farmacologia , Tromboplastina/antagonistas & inibidores , Animais , Doença da Artéria Coronariana/metabolismo , Vasos Coronários/metabolismo , Masculino , Período Pós-Operatório , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Tromboplastina/metabolismo , Transplante Homólogo
17.
Transplantation ; 69(9): 1830-6, 2000 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-10830219

RESUMO

BACKGROUND: 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been shown to reduce cardiac allograft failure and to lower the incidence of transplant coronary artery disease. These effects result from as yet unknown mechanisms not clearly attributable to lipid lowering. We here report that low-dose simvastatin treatment inhibits excessive expression of monocyte tissue factor (TF) and reduces the persistent hypercoagulability state seen in cardiac transplant recipients. METHODS: Fifteen consecutive heart transplant recipients receiving standard oral immunosuppression were newly assigned to a 10 mg daily simvastatin therapy. Levels of TF activity in both unstimulated and lipopolysaccharide-stimulated peripheral blood mononuclear cells drawn from transplant recipients before and under simvastatin therapy were evaluated by one-stage clotting assay. RESULTS: Monocyte TF activity was found to be significantly increased in cardiac transplant recipients when compared with healthy controls. Excessive monocyte procoagulant activity was reduced in cardiac transplant recipients during simvastatin treatment. This effect occurred independently of the reduction of serum low-density lipoprotein cholesterol. As demonstrated by reverse transcriptase-polymerase chain reaction, monocyte TF reduction by simvastatin, observed in 13 of the 15 transplant recipients investigated, could be ascribed to an inhibition of monocyte TF gene transcription. The reduction of monocyte TF activity during treatment with simvastatin paralleled with the normalization of elevated levels of thrombin-antithrombin complex, prothrombin fragment F1+2, and D-dimer, which are markers of thrombin and fibrin formation indicating coagulation activation after cardiac transplantation. CONCLUSION: Inhibition of monocyte TF expression and attenuation of the persistent hypercoagulable state observed in cardiac transplant recipients during treatment with simvastatin may represent an important mechanism by which HMG-CoA reductase inhibitors protect against the development of transplant coronary artery disease.


Assuntos
Transtornos da Coagulação Sanguínea/tratamento farmacológico , Doença das Coronárias/prevenção & controle , Transplante de Coração/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Sinvastatina/uso terapêutico , Adulto , Idoso , Feminino , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Monócitos/química , RNA Mensageiro/análise , Tromboplastina/análise , Tromboplastina/genética
19.
Thromb Haemost ; 82(6): 1614-20, 1999 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-10613644

RESUMO

The association between use of oral contraceptives (OCs) and increased risk of thromboembolic disease has been firmly established. This risk increases when use of OCs is combined with cigarette smoking. The cellular mechanism favoring an hypercoagulable state under these behaviours is not known. Circulating monocytes are potent activators of the coagulation cascade through their ability to synthesize procoagulant tissue factor (TF). In the present study we report that monocyte TF expression is increased in women who use OCs and smoke. We studied monocyte TF expression in 4 groups of healthy pre-menopausal women (n = 15 each): (1) non-smoking OC non-users, (2) nonsmoking current OC users, (3) smoking OC non-users and (4) smoking OC users. TF expression was assessed on both mRNA and protein levels in unstimulated and LPS-stimulated cells. Transcriptional activation of the TF gene was assessed by analysis of the transcription factor NF-kappaB and its inhibitor molecule IkappaBalpha. Monocyte TF generation was significantly higher in OC users than in women who did not use OCs. Enhanced monocyte TF generation was also observed in smoking women when compared to non-smokers. Strongest monocyte TF expression occurred in women with combined smoking and use of OCs. The enhanced TF expression in monocytes from women using OCs or smoking was based on an increased TF gene transcription following activation of NF-kappaB. Experiments on cultured monocytes/macrophages demonstrated enhanced IkappaBalpha degradation in the presence of estradiol, suggesting that a direct hormone effect is responsible for the observed increase in monocyte TF expression. This study demonstrates that use of OCs and smoking is associated with an increase in monocyte TF expression in pre-menopausal women. Aberrant TF expression by blood monocytes may favour intravascular clotting activation in women with OC therapy. The further enhancement of TF activity observed in women who smoke and use OCs may explain the synergistic effect of smoking on risk of thromboembolic events associated with contraceptive use.


Assuntos
Anticoncepcionais Orais , Monócitos/metabolismo , Fumar , Tromboplastina/biossíntese , Adolescente , Adulto , Anticoncepcionais Orais/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Pré-Menopausa , Fumar/efeitos adversos , Trombose/etiologia
20.
Am J Physiol ; 276(6): H1892-901, 1999 06.
Artigo em Inglês | MEDLINE | ID: mdl-10362668

RESUMO

We investigated the relationship between the ATP-evoked rise of cytosolic Ca2+ concentration ([Ca2+]i) and barrier function in porcine aortic endothelial monolayers. ATP (0.01-100 microM) induced a transient rise of [Ca2+]i and reduced permeability in a concentration-dependent manner. In contrast, the Ca2+ ionophore ionomycin (1 microM) elicited a rise in [Ca2+]i comparable to that induced by ATP (10 microM), but it increased permeability. For the reduction of permeability, nucleotides were found to be in the following order of potency: ATP = ATPgammaS > ADP = UTP. Blockade of adenosine receptors by 8-phenyltheophylline (10 microM) did not affect ATP (10 microM)-induced reduction of permeability. ATP reduced permeability even in endothelial monolayers that had been loaded with the Ca2+ chelator BAPTA to prevent the rise in [Ca2+]i. U-73122 (1 microM), an inhibitor of phospholipase C (PLC), completely abolished the effect of ATP (10 microM) on permeability. It also abolished the translocation of protein kinase C (PKC) in response to ATP, which could also be achieved by the PKC inhibitors Gö-6976 (100 nM) or bisindolylmaleimide I (1 microM). In the presence of PKC inhibitors, however, the permeability effect of ATP was not affected. The presence of inhibitors of adenylate or guanylate cyclase (50 microM SQ-22536 or 20 microM ODQ) prevented changes in cyclic nucleotides but did not affect the permeability effects of ATP. The study shows that ATP reduces macromolecule permeability via a PLC-mediated mechanism that is independent of the concomitant effects of ATP on cytosolic Ca2+, cyclic nucleotides, or PKC.


Assuntos
Trifosfato de Adenosina/farmacologia , Cálcio/metabolismo , Permeabilidade Capilar/fisiologia , Endotélio Vascular/metabolismo , Animais , Permeabilidade Capilar/efeitos dos fármacos , Bovinos , Células Cultivadas , Citosol/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Humanos , Substâncias Macromoleculares , Nucleotídeos Cíclicos/metabolismo , Concentração Osmolar , Proteína Quinase C/metabolismo , Suínos , Fosfolipases Tipo C/metabolismo
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