Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Más filtros

Banco de datos
Tipo de estudio
Tipo del documento
País de afiliación
Intervalo de año de publicación
1.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artículo en Inglés | MEDLINE | ID: mdl-34360813

RESUMEN

Proper cardiac function depends on the coordinated expression of multiple gene networks related to fuel utilization and mitochondrial ATP production, heart contraction, and ion transport. Key transcriptional regulators that regulate these gene networks have been identified. Among them, estrogen-related receptors (ERRs) have emerged as crucial modulators of cardiac function by regulating cellular metabolism and contraction machinery. Consistent with this role, lack of ERRα or ERRγ results in cardiac derangements that lead to functional maladaptation in response to increased workload. Interestingly, metabolic inflexibility associated with diabetic cardiomyopathy has been recently associated with increased mitochondrial fatty acid oxidation and expression of ERRγ, suggesting that sustained expression of this nuclear receptor could result in a cardiac pathogenic outcome. Here, we describe the generation of mice with cardiac-specific overexpression of ERRγ, which die at young ages due to heart failure. ERRγ transgenic mice show signs of dilated cardiomyopathy associated with cardiomyocyte hypertrophy, increased cell death, and fibrosis. Our results suggest that ERRγ could play a role in mediating cardiac pathogenic responses.


Asunto(s)
Cardiomiopatía Dilatada/metabolismo , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Receptores de Estrógenos/fisiología , Animales , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Miocardio/patología , Miocitos Cardíacos/patología
2.
Mol Cell Endocrinol ; 430: 77-88, 2016 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-27062900

RESUMEN

Diabetic cardiomyopathy is characterized by an abnormal oxidative metabolism, but the underlying mechanisms remain to be defined. To uncover potential mechanisms involved in the pathophysiology of diabetic cardiomyopathy, we performed a gene expression profiling study in hearts of diabetic db/db mice. Diabetic hearts showed a gene expression pattern characterized by the up-regulation of genes involved in lipid oxidation, together with an abnormal expression of genes related to the cardiac contractile function. A screening for potential regulators of the genes differentially expressed in diabetic mice found that estrogen-related receptor γ (ERRγ) was increased in heart of db/db mice. Overexpression of ERRγ in cultured cardiomyocytes was sufficient to promote the expression of genes involved in lipid oxidation, increase palmitate oxidation and induce cardiomyocyte hypertrophy. Our findings strongly support a role for ERRγ in the metabolic alterations that underlie the development of diabetic cardiomyopathy.


Asunto(s)
Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patología , Cardiomiopatías Diabéticas/genética , Cardiomiopatías Diabéticas/patología , Perfilación de la Expresión Génica , Miocardio/metabolismo , Receptores de Estrógenos/metabolismo , Animales , Cardiomegalia/genética , Cardiomegalia/patología , Diabetes Mellitus Experimental/fisiopatología , Cardiomiopatías Diabéticas/diagnóstico por imagen , Cardiomiopatías Diabéticas/fisiopatología , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Metabolismo de los Lípidos/genética , Masculino , Miocardio/patología , Miocitos Cardíacos/metabolismo , PPAR alfa/metabolismo , Regiones Promotoras Genéticas/genética
3.
PLoS One ; 6(11): e26989, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-22087241

RESUMEN

BACKGROUND: Thiazolidinediones, a family of insulin-sensitizing drugs commonly used to treat type 2 diabetes, are thought to exert their effects in part by promoting mitochondrial biogenesis in white adipose tissue through the transcriptional coactivator PGC-1α (Peroxisome Proliferator-Activated Receptor γ Coactivator-1α). METHODOLOGY/PRINCIPAL FINDINGS: To assess the role of PGC-1α in the control of rosiglitazone-induced mitochondrial biogenesis, we have generated a mouse model that lacks expression of PGC-1α specifically in adipose tissues (PGC-1α-FAT-KO mice). We found that expression of genes encoding for mitochondrial proteins involved in oxidative phosphorylation, tricarboxylic acid cycle or fatty acid oxidation, was similar in white adipose tissue of wild type and PGC-1α-FAT-KO mice. Furthermore, the absence of PGC-1α did not prevent the positive effect of rosiglitazone on mitochondrial gene expression or biogenesis, but it precluded the induction by rosiglitazone of UCP1 and other brown fat-specific genes in white adipose tissue. Consistent with the in vivo findings, basal and rosiglitazone-induced mitochondrial gene expression in 3T3-L1 adipocytes was unaffected by the knockdown of PGC-1α but it was impaired when PGC-1ß expression was knockdown by the use of specific siRNA. CONCLUSIONS/SIGNIFICANCE: These results indicate that in white adipose tissue PGC-1α is dispensable for basal and rosiglitazone-induced mitochondrial biogenesis but required for the rosiglitazone-induced expression of UCP1 and other brown adipocyte-specific markers. Our study suggests that PGC-1α is important for the appearance of brown adipocytes in white adipose tissue. Our findings also provide evidence that PGC-1ß and not PGC-1α regulates basal and rosiglitazone-induced mitochondrial gene expression in white adipocytes.


Asunto(s)
Tejido Adiposo Blanco/metabolismo , Mitocondrias/metabolismo , Tiazolidinedionas/farmacología , Transactivadores/fisiología , Tejido Adiposo Blanco/ultraestructura , Animales , Regulación de la Expresión Génica/efectos de los fármacos , Hipoglucemiantes , Ratones , Mitocondrias/efectos de los fármacos , Proteínas Mitocondriales/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , ARN Interferente Pequeño/farmacología , Rosiglitazona , Factores de Transcripción
4.
Mol Cancer Res ; 8(11): 1489-500, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21106507

RESUMEN

Metastasis is the final stage of tumor progression and is thought to be responsible for up to 90% of deaths associated with solid tumors. Caveolin-1 (CAV1) regulates multiple cancer-associated processes related to malignant tumor progression. In the present study, we tested the hypothesis that CAV1 modulates the metastatic ability of cells from the Ewing's sarcoma family of tumors (ESFT). First, we analyzed the expression of CAV1 by immunostaining a tissue microarray containing 43 paraffin-embedded ESFT tumors with known EWS translocations. Even though no evidence was found for a significant association between CAV1 expression and stage, size or tumor site, all metastatic samples (10 of 10) had significantly high CAV1 expression, suggesting that high CAV1 content could positively contribute to enhance ESFT metastasis. To determine the effect of CAV1 on the migratory and invasive capabilities of ESFT cells, we knocked down CAV1 expression in TC252 and A673 cells by stably transfecting a previously validated shRNA construct. In vitro, migration and invasion assays showed that for both cell lines, CAV1 knocked-down cells migrated and invaded significantly less (P ≤ 0.01) than control cells. Moreover, control A673 cells introduced into BALB/c nude mice by tail vein injection strongly colonized the lungs. In contrast, animals injected with CAV1 knocked-down cells showed either no incidence of metastasis or developed lung metastases after a significant delay (P < 0.0001). Finally, we show that the molecular mechanisms by which CAV1 carries out its key role in regulating ESFT metastasis involve matrix metalloproteinase production and activation as well as the control of the expression of SPARC, a known determinant of lung colonization.


Asunto(s)
Neoplasias Óseas/patología , Caveolina 1/biosíntesis , Neoplasias Pulmonares/secundario , Sarcoma de Ewing/patología , Animales , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Caveolina 1/genética , Línea Celular Tumoral , Movimiento Celular/fisiología , Proteínas Activadoras de GTPasa/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Metaloproteinasa 14 de la Matriz/metabolismo , Metaloproteasas/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Sarcoma de Ewing/genética , Sarcoma de Ewing/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA