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1.
Circ Res ; 86(12): 1224-9, 2000 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-10864912

RESUMO

We investigated the role of heme oxygenase (HO)-1 in the development of hypoxia-induced pulmonary hypertension. HO catalyzes the breakdown of heme to the antioxidant bilirubin and the vasodilator carbon monoxide. Hypoxia is a potent but transient inducer of HO-1 in vascular smooth muscle cells in vitro and in the lung in vivo. By using agonists of HO-1, we sustained a high expression of HO-1 in the lungs of rats for 1 week. We report that this in vivo enhancement of HO-1 in the lung prevented the development of hypoxic pulmonary hypertension and inhibited the structural remodeling of the pulmonary vessels. The mechanism(s) underlying this effect may involve a direct vasodilating and antiproliferative action of endogenous carbon monoxide, as well as an indirect effect of carbon monoxide on the production of vasoconstrictors. These results provide evidence that enhancement of endogenous adaptive responses may be used to prevent hypoxia-induced pulmonary hypertension.


Assuntos
Heme Oxigenase (Desciclizante)/metabolismo , Hipertensão Pulmonar/prevenção & controle , Hipóxia/enzimologia , Animais , Circulação Sanguínea/fisiologia , Vasos Sanguíneos/fisiopatologia , GMP Cíclico/sangue , Regulação da Expressão Gênica , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase (Desciclizante)/fisiologia , Heme Oxigenase-1 , Hipertensão Pulmonar/etiologia , Hipóxia/complicações , Pulmão/metabolismo , Pulmão/fisiologia , Masculino , Circulação Pulmonar/fisiologia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley
2.
J Biol Chem ; 273(32): 20341-6, 1998 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-9685385

RESUMO

The CD44 gene codes for a family of alternatively spliced, multifunctional adhesion molecules that participate in extracellular matrix binding, lymphocyte activation, cell migration, and tumor metastasis. In a mouse model of transplant-associated arteriosclerosis, CD44 protein was induced in the neointima of allografted vessels and colocalized with a subset of proliferating vascular smooth muscle cells (SMC). To elucidate the molecular mechanisms regulating CD44 expression in this model, we investigated the regulation of CD44 gene expression by interleukin (IL)-1beta. Treatment of rat aortic SMC with IL-1beta resulted in a 5.3-fold increase in cell surface CD44 expression. Northern analysis showed that IL-1beta promoted a dose- and time-dependent induction of CD44 mRNA which reached 6.6-fold after 48 h, and nuclear run-on analysis showed that IL-1beta increased the rate of CD44 gene transcription within 8 h of stimulation. In transient reporter gene transfection experiments in rat aortic SMC, a 1.4-kilobase fragment of the mouse CD44 5'-flanking sequence mediated this response to IL-1beta. Regulation of CD44 gene expression by the proinflammatory cytokine IL-1beta may contribute to SMC phenotypic modulation in the pathogenesis of arteriosclerosis.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Receptores de Hialuronatos/genética , Interleucina-1/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Animais , Aorta/citologia , Aorta/fisiologia , Arteriosclerose/fisiopatologia , Sequência de Bases , Moléculas de Adesão Celular/fisiologia , Células Cultivadas , Modelos Animais de Doenças , Genes Reporter/genética , Imuno-Histoquímica , Camundongos , Dados de Sequência Molecular , Regiões Promotoras Genéticas/genética , RNA Mensageiro/metabolismo , Ratos , Análise de Sequência de DNA , Transplante Homólogo/imunologia
3.
Circ Res ; 82(8): 845-51, 1998 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-9576104

RESUMO

We identified the cell surface glycoprotein Thy-1 on the endothelium of newly formed blood vessels in four models of angiogenesis in adult rats. Anti-Thy-1 staining showed that Thy-1 was upregulated in adventitial blood vessels after balloon injury to the carotid artery. Preabsorption with a rat Thy-1-Ig fusion construct eliminated all immunoreactivity and thus confirmed the specificity of the Thy-1 staining. Thy-1 was also expressed in the endothelium of small blood vessels formed after tumor implantation in the cornea, in periureteral vessels formed after ligation of the renal artery, and in small blood vessels of the uterus formed during pregnancy. In contrast with its expression during adult angiogenesis, Thy-1 was not expressed in the endothelium of blood vessels during embryonic angiogenesis. In vitro, the inflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha upregulated Thy-1 mRNA by 8- and 14-fold, respectively. Vascular endothelial growth factor, basic fibroblast growth factor, transforming growth factor-beta, and platelet-derived growth factor-BB had no effect on Thy-1 mRNA. Thus, Thy-1 appears to be a marker of adult but not embryonic angiogenesis. The upregulation of Thy-1 by cytokines but not growth factors indicates the importance of inflammation in the pathogenesis of adult angiogenesis.


Assuntos
Lesões das Artérias Carótidas , Córnea/irrigação sanguínea , Citocinas/farmacologia , Endotélio Vascular/fisiopatologia , Regulação da Expressão Gênica , Glioblastoma/irrigação sanguínea , Neovascularização Patológica , Neovascularização Fisiológica , Obstrução da Artéria Renal/fisiopatologia , Antígenos Thy-1/biossíntese , Angioplastia com Balão , Animais , Biomarcadores , Artérias Carótidas/imunologia , Artérias Carótidas/patologia , Córnea/imunologia , Córnea/patologia , Desenvolvimento Embrionário e Fetal , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/imunologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Glioblastoma/imunologia , Imuno-Histoquímica , Inflamação , Interleucina-1/farmacologia , Masculino , Gravidez , Ratos , Ratos Sprague-Dawley , Obstrução da Artéria Renal/imunologia , Antígenos Thy-1/análise , Transcrição Gênica/efeitos dos fármacos , Transcrição Gênica/imunologia , Fator de Necrose Tumoral alfa/biossíntese , Fator de von Willebrand/análise , Fator de von Willebrand/biossíntese
4.
J Biol Chem ; 273(8): 4400-5, 1998 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-9468491

RESUMO

Although several cytokines and growth factors have been shown to regulate vascular endothelial growth factor (VEGF) production, little is known about how VEGF may regulate growth factors that have known mitogenic and chemotactic actions on mesenchymal cells (which are involved in the maturation of the angiogenic process). We investigated the effect of VEGF on heparin-binding epidermal growth factor-like growth factor (HB-EGF) expression in human umbilical vein endothelial cells. HB-EGF mRNA was induced by 8-fold after 2 h of VEGF stimulation, and it returned to base line within 6 h. VEGF did not alter the half-life of HB-EGF mRNA (55 min). Nuclear run-on experiments showed a 4.9-fold increase in HB-EGF gene transcription within 2 h of VEGF stimulation, and Western analysis demonstrated an associated increase in cellular HB-EGF protein. We found that platelet-derived growth factor-BB (PDGF-BB) mRNA was also induced 3-fold after 5 h of VEGF stimulation, whereas neither endothelin 1 nor transforming growth factor-beta1 was regulated by VEGF. Finally, conditioned medium from VEGF-stimulated endothelial cells produced an increase in DNA synthesis in vascular smooth muscle cells, and this effect was blocked by a neutralizing antibody to PDGF. The induction of HB-EGF and PDGF-BB expression in endothelial cells may represent the mechanism by which VEGF recruits mesenchymal cells to form the medial and adventitial layers of arterioles and venules during the course of angiogenesis.


Assuntos
Fatores de Crescimento Endotelial/metabolismo , Endotélio Vascular/metabolismo , Fator de Crescimento Epidérmico/biossíntese , Linfocinas/metabolismo , Movimento Celular , Células Cultivadas , Meios de Cultivo Condicionados , Endotélio Vascular/citologia , Fator de Crescimento Epidérmico/genética , Regulação da Expressão Gênica , Fator de Crescimento Semelhante a EGF de Ligação à Heparina , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcrição Gênica , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular
5.
J Heart Lung Transplant ; 16(10): 1035-45, 1997 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9361246

RESUMO

BACKGROUND: Cytomegalovirus has been implicated in the development of allograft vasculopathy in heart transplant recipients. Given that allograft vasculopathy is a form of chronic rejection, it is conceivable that cytomegalovirus somehow alters the allogeneic response to the vasculature. Prior work has demonstrated that smooth muscle cells (SMCs) are highly permissive for cytomegalovirus and exhibit cytopathologic characteristics and alterations in MHC class I antigens in response to cytomegalovirus at a high multiplicity of infection (MOI). METHODS: To determine whether cytomegalovirus at low, more clinically relevant MOI, can alter SMCs phenotypically, human aortic SMCs were infected with approximately 1 plaque forming units/3000 cells of cytomegalovirus strain AD169. RESULTS: One week after infection, human aortic SMCs (compared with human foreskin fibroblasts) demonstrated no cytopathologic characteristics (n = 6), released reduced amounts of intact virion into the culture media (assessed by exposing naive monolayers of human foreskin fibroblasts to media and staining for cytomegalovirus immediate-early antigen, n = 3), yet had at least, if not greater detectable total cytomegalovirus vital DNA levels. Infected HASMCs uniformly increased their expression of MHC class I antigen by 55% +/- 21% above constitutive levels (assessed by flow cytometry (n = 5, p < 0.0001). Cytomegalovirus infection resulted in an increase in interleukin-6 mRNA expression compared to control (297 +/- 63 vs 188 +/- 50, respectively; p = 0.02, n = 6) and reduced the expression of transforming growth factor-beta mRNA (802 +/- 152 vs 1201 +/- 236, respectively; p = 0.05). CONCLUSIONS: These data suggest that low MOI of cytomegalovirus can infect SMCs without producing cell cytolysis and, in spite of this lack of overt infection, modulate cell surface antigens and cytokine mRNA levels that can influence allogeneic responses.


Assuntos
Doenças da Aorta/virologia , Citocinas/análise , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Antígenos de Histocompatibilidade Classe I/análise , Músculo Liso Vascular/virologia , Antígenos Virais/análise , Antígenos Virais/imunologia , Doenças da Aorta/imunologia , Células Cultivadas , Doença Crônica , Corantes , Doença das Coronárias/virologia , Meios de Cultura , Citocinas/imunologia , Citomegalovirus/fisiologia , Efeito Citopatogênico Viral , DNA Viral/análise , Fibroblastos/imunologia , Fibroblastos/virologia , Regulação Viral da Expressão Gênica , Rejeição de Enxerto/virologia , Transplante de Coração/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Proteínas Imediatamente Precoces/análise , Proteínas Imediatamente Precoces/imunologia , Interleucina-6/análise , Interleucina-6/genética , Músculo Liso Vascular/imunologia , Fenótipo , RNA Mensageiro/análise , RNA Mensageiro/genética , Fator de Crescimento Transformador beta/análise , Fator de Crescimento Transformador beta/genética , Transplante Homólogo , Vírion/metabolismo , Replicação Viral
6.
Pharmacology ; 52(2): 92-100, 1996 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-8851630

RESUMO

The systemic and coronary hemodynamic effects of the nitrovasodilator, pirsidomine, were compared with SIN-1, nitroprusside, and nitroglycerin. Four groups consisting of 32 experiments were performed in 17 conscious dogs chronically instrumented for measurement of aortic and left ventricular pressure, left ventricular dP/dtmax, diastolic coronary blood flow velocity, cardiac output, and subendocardial segment length. On separate experimental days, systemic and coronary hemodynamics were recorded during control conditions and after intravenous administration of pirsidomine (1.0, 2.0, and 4.0 mg.kg-1), SIN-1, (50, 100, and 200 micrograms.kg-1), nitroprusside (0.5, 1.0, and 2.0 micrograms.kg-1.min-1), or nitroglycerin (1.0, 2.0, and 4.0 micrograms.kg-1.min-1). Pirsidomine decreased mean arterial, left ventricular systolic and end-diastolic pressures, stroke volume and systemic vascular resistance. Diastolic coronary blood flow velocity and heart rate were increased and coronary vascular resistance decreased by pirsidomine. SIN-1, nitroprusside and nitroglycerin caused similar decreases in preload (evaluated by left ventricular end-diastolic pressure) and afterload (indirectly assessed by mean arterial pressure and systemic vascular resistance) as compared to pirsidomine. However, equihypotensive doses of SIN-1, nitroprusside, and nitroglycerin improved ventricular performance as assessed by increases in left ventricular dP/dtmax, cardiac output and segment shortening, in contrast to those findings during comparable doses of pirsidomine (4 mg.kg-1). Despite similar loading conditions, high doses of pirsidomine did not enhance left ventricular function, suggesting that pirsidomine may have direct negative inotropic effects.


Assuntos
Hemodinâmica/efeitos dos fármacos , Óxido Nítrico/metabolismo , Sidnonas/farmacologia , Vasodilatadores/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Cães , Frequência Cardíaca/efeitos dos fármacos , Injeções Intravenosas , Molsidomina/administração & dosagem , Molsidomina/análogos & derivados , Molsidomina/farmacologia , Nitroglicerina/administração & dosagem , Nitroglicerina/farmacologia , Nitroprussiato/administração & dosagem , Nitroprussiato/farmacologia , Sidnonas/administração & dosagem , Vasodilatadores/administração & dosagem
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