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1.
J Am Heart Assoc ; 3(4)2014 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-25015075

RESUMO

BACKGROUND: Right ventricular (RV) failure is a major cause of mortality worldwide and is often a consequence of RV pressure overload (RVPO). Endoglin is a coreceptor for the profibrogenic cytokine, transforming growth factor beta 1 (TGF-ß1). TGF-ß1 signaling by the canonical transient receptor protein channel 6 (TRPC-6) was recently reported to stimulate calcineurin-mediated myofibroblast transformation, a critical component of cardiac fibrosis. We hypothesized that reduced activity of the TGF-ß1 coreceptor, endoglin, limits RV calcineurin expression and improves survival in RVPO. METHODS AND RESULTS: We first demonstrate that endoglin is required for TGF-ß1-mediated calcineurin/TRPC-6 expression and up-regulation of alpha-smooth muscle antigen (α-SMA), a marker of myofibroblast transformation, in human RV fibroblasts. Using endoglin haploinsufficient mice (Eng(+/-)) we show that reduced endoglin activity preserves RV function, limits RV fibrosis, and attenuates activation of the calcineurin/TRPC-6/α-SMA pathway in a model of angio-obliterative pulmonary hypertension. Next, using Eng(+/-) mice or a neutralizing antibody (Ab) against endoglin (N-Eng) in wild-type mice, we show that reduced endoglin activity improves survival and attenuates RV fibrosis in models of RVPO induced by pulmonary artery constriction. To explore the utility of targeting endoglin, we observed a reversal of RV fibrosis and calcineurin levels in wild-type mice treated with a N-Eng Ab, compared to an immunoglobulin G control. CONCLUSION: These data establish endoglin as a regulator of TGF-ß1 signaling by calcineurin and TRPC-6 in the RV and identify it as a potential therapeutic target to limit RV fibrosis and improve survival in RVPO, a common cause of death in cardiac and pulmonary disease.


Assuntos
Calcineurina/genética , Hipertensão Pulmonar/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , RNA Mensageiro/metabolismo , Canais de Cátion TRPC/genética , Disfunção Ventricular Direita/genética , Actinas/genética , Actinas/metabolismo , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Calcineurina/metabolismo , Modelos Animais de Doenças , Endoglina , Fibroblastos/metabolismo , Ventrículos do Coração/citologia , Ventrículos do Coração/metabolismo , Humanos , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Camundongos Knockout , Miofibroblastos/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Transdução de Sinais , Taxa de Sobrevida , Canais de Cátion TRPC/metabolismo , Canal de Cátion TRPC6 , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Disfunção Ventricular Direita/metabolismo , Disfunção Ventricular Direita/fisiopatologia
2.
PLoS One ; 8(7): e70802, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23936252

RESUMO

UNLABELLED: Right ventricular (RV) failure is a major cause of mortality in acute or chronic lung disease and left heart failure. The objective of this study was to demonstrate a percutaneous approach to study biventricular hemodynamics in murine models of primary and secondary RV pressure overload (RVPO) and further explore biventricular expression of two key proteins that regulate cardiac remodeling: calcineurin and transforming growth factor beta 1 (TGFß1). METHODS: Adult, male mice underwent constriction of the pulmonary artery or thoracic aorta as models of primary and secondary RVPO, respectively. Conductance catheterization was performed followed by tissue analysis for changes in myocyte hypertrophy and fibrosis. RESULTS: Both primary and secondary RVPO decreased biventricular stroke work however RV instantaneous peak pressure (dP/dtmax) and end-systolic elastance (Ees) were preserved in both groups compared to controls. In contrast, left ventricular (LV) dP/dtmax and LV-Ees were unchanged by primary, but reduced in the secondary RVPO group. The ratio of RV:LV ventriculo-arterial coupling was increased in primary and reduced in secondary RVPO. Primary and secondary RVPO increased RV mass, while LV mass decreased in primary and increased in the secondary RVPO groups. RV fibrosis and hypertrophy were increased in both groups, while LV fibrosis and hypertrophy were increased in secondary RVPO only. RV calcineurin expression was increased in both groups, while LV expression increased in secondary RVPO only. Biventricular TGFß1 expression was increased in both groups. CONCLUSION: These data identify distinct effects of primary and secondary RVPO on biventricular structure, function, and expression of key remodeling pathways.


Assuntos
Disfunção Ventricular Direita/patologia , Disfunção Ventricular Direita/fisiopatologia , Pressão Ventricular , Remodelação Ventricular , Animais , Calcineurina/metabolismo , Modelos Animais de Doenças , Fibrose , Sistema de Condução Cardíaco , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Hemodinâmica , Masculino , Camundongos , Tamanho do Órgão , Fator de Crescimento Transformador beta1/metabolismo , Disfunção Ventricular Direita/metabolismo
3.
Circulation ; 128(4): 328-36, 2013 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-23766351

RESUMO

BACKGROUND: Ischemia/reperfusion injury worsens infarct size, a major determinant of morbidity and mortality after acute myocardial infarction (MI). We tested the hypothesis that reducing left ventricular wall stress with a percutaneous left atrial-to-femoral artery centrifugal bypass system while delaying coronary reperfusion limits myocardial injury in a model of acute MI. METHODS AND RESULTS: MI was induced by balloon occlusion of the left anterior descending artery in adult male swine. In the MI group (n=4), 120 minutes of left anterior descending artery occlusion was followed by 120 minutes of reperfusion without mechanical support. In the mechanically supported group (MI+unload; n=4), percutaneous left atrial-to-femoral artery bypass was initiated after 120 minutes of ischemia, and left anterior descending artery occlusion was prolonged for an additional 30 minutes, followed by 120 minutes of reperfusion with device support. All animals were euthanized after reperfusion, and infarct size was quantified by triphenyltetrazolium chloride staining. Compared with baseline, mean left ventricular wall stress and stroke work were not changed at any point in the MI group but were decreased after reperfusion in the MI+unload group (mean left ventricular wall stress, 44 658 versus 22 963 dynes/cm(2); stroke work, 2823 versus 655 mm Hg·mL, MI versus MI+unload). Phosphorylation of reperfusion injury salvage kinase pathway proteins from noninfarcted left ventricular tissue was unchanged in the MI group but was increased in the MI+unload group. Compared with the MI group, total infarct size was reduced in the MI+unload group (49% versus 28%, MI versus MI+unload). CONCLUSIONS: These data support that first unloading the left ventricle despite delaying coronary reperfusion during an acute MI reduces myocardial injury.


Assuntos
Coração Auxiliar , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/terapia , Reperfusão Miocárdica , Função Ventricular Esquerda/fisiologia , Animais , Modelos Animais de Doenças , Ecocardiografia Tridimensional , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Hemodinâmica/fisiologia , Masculino , Infarto do Miocárdio/diagnóstico por imagem , Traumatismo por Reperfusão Miocárdica/diagnóstico por imagem , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Traumatismo por Reperfusão Miocárdica/terapia , Estresse Mecânico , Sus scrofa
4.
Matrix Biol ; 31(2): 120-34, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22222602

RESUMO

Laminins are heterotrimeric extracellular glycoproteins found in, but not confined to, basement membranes (BMs). They are important components in formation of the molecular networks of BMs as well as in cell polarity, cell differentiation and tissue morphogenesis. Each laminin is composed by an α, a ß and a γ chain. Previous studies have shown that the γ3 chain is partnered with either the ß1 chain (in placenta) or ß2 chain (in the CNS) (Libby et al., 2000). Several studies, including our own, suggested that the γ3 chain is expressed in both apical and basal compartments (Koch et al., 1999; Gersdorff et al., 2005; Yan and Cheng, 2006). This study investigates the expression pattern of the γ3 chain in mouse. We developed three new γ3-reactive antibodies, and we show that the γ3 chain is present in BMs. The distribution pattern is considerably more restricted than that of the γ1 chain and within any tissue there is differential deposition into BM compartments. This is particularly true in the retina and brain, where γ3 is uniquely expressed in a subset of the vascular basement membranes and the pial surface. We used conventional genetic ablation techniques to remove the γ3 chain in mice; unlike other laminin null mice (α5, ß2, γ1 nulls), these mice live a normal lifespan and have only minor abnormalities, the most striking of which are ectopic granule cells in the cerebellum and an apparent increase in capillary branching in the outer retina. These data support the suggestion that the γ3 chain is deposited in BMs and contributes some unique properties to their function, particularly in the nervous system.


Assuntos
Membrana Basal/metabolismo , Regulação da Expressão Gênica , Laminina/metabolismo , Alelos , Animais , Anticorpos/metabolismo , Membrana Basal/citologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Clonagem Molecular , Heterozigoto , Imuno-Histoquímica , Integrina beta1/genética , Integrina beta1/metabolismo , Laminina/genética , Longevidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Neurônios/citologia , Neurônios/metabolismo , Coelhos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Retina/metabolismo , Retina/patologia , Neovascularização Retiniana/metabolismo , Neovascularização Retiniana/patologia
5.
Vis Neurosci ; 21(6): 925-34, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15733347

RESUMO

Significant variation in absolute dark-adapted thresholds is observed both within and between strains of mice with differing ocular pigmentation levels. Differences in threshold within a single strain are related to the Williams' photostasis effect, that is, photoreceptor rhodopsin levels are dependent upon ambient lighting conditions. To examine threshold differences among strains, we equalized rhodopsin levels by maintaining albino mice (c2J/c2J) at 2 x 10-4 cd/m2 (dim light) and black mice at 2 x 102 cd/m2 (bright light). This resulted in ocular rhodopsin levels for albino mice (albino--dim) of 494 +/- 11 pmoles/eye and rhodopsin levels for black mice (black--bright) of 506 +/- 25 pmoles/eye. For comparison, rhodopsin levels in black mice maintained in dim light are 586 +/- 46 pmoles/eye and 217 +/- 46 pmoles/eye in albino mice maintained in bright light. We found similar dark-adapted thresholds (6.38 log cd/m2 vs. 6.47 log cd/m2)) in albino and black mice with equivalent rhodopsin determined with a water maze test. This suggests that dark-adapted thresholds are directly related to rhodopsin levels regardless of the level of ocular melanin. The number of photoreceptors, photoreceptor layer thickness, and outer segment length did not differ significantly between albino (dark) and black mice (bright). These results demonstrate that the visual sensitivity defect found in hypopigmented animals is secondary to abnormal rhodopsin regulation and that hypopigmented animals have either an improper input to the photostasis mechanism or that the photostasis mechanism is defective.


Assuntos
Albinismo/fisiopatologia , Adaptação à Escuridão , Iluminação , Pigmentação , Rodopsina/metabolismo , Limiar Sensorial , Visão Ocular , Adaptação Ocular , Albinismo/metabolismo , Animais , Olho/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Reflexo Pupilar , Especificidade da Espécie
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