Nuestros investigadores

Carlos de Miguel Vázquez

Bioquímica y Genética
Facultad de Ciencias. Universidad de Navarra
Líneas de investigación
Identificación de nuevos genes de la familia de las MAP-quinasas. Caracterización de la estructura de los genes de ERK1 de rata y p44mapk humana. Estudio de la regulación de la expresión del gen de la p44mapk humana. Análisis de su promotor, Estudio de la regulación de la expresión del gen del receptor de glucocorticoides humano (hGR). Clonado, caracterización y estudio de la regulación de la expresión de los genes de los receptores de retinoides humanos (hRXRalfa y hRXRbeta), Estudio del proceso de activación y diferenciación de células del sistema inmune inducido por péptidos sintéticos con secuencias derivadas de prot. Identificación de genes con expresión diferencial en el monocito. Relación con las enfermedades autoinmunes, Identificación de genes con expresión diferencial en el desarrollo de la obesidad inducida por una dieta rica en grasa en un modelo animal., Regulación de la expresión de los genes de las caveolinas en un modelo de obesidad inducido por una dieta hipercalórica rica en grasa. Relación con la señalización insulínica., Regulación epigenética de la caveolina-1 durante la adipogénesis. Relación con la señalización insulínica

Publicaciones científicas más recientes (desde 2010)

Autores: Marques, J.; Pejenaute, Álvaro; et al.
Revista: CELLS
ISSN 2073-4409  Vol. 9  Nº 3  2020  págs. 637
Oxidative stress is a main molecular mechanism that underlies cardiovascular diseases. A close relationship between reactive oxygen species (ROS) derived from NADPH oxidase (NOX) activity and the prostaglandin (PG) biosynthesis pathway has been described. However, little information is available about the interaction between NOX5 homolog-derived ROS and the PG pathway in the cardiovascular context. Our main goal was to characterize NOX5-derived ROS effects in PG homeostasis and their potential relevance in cardiovascular pathologies. For that purpose, two experimental systems were employed: an adenoviral NOX5-beta overexpression model in immortalized human aortic endothelial cells (TeloHAEC) and a chronic infarction in vivo model developed from a conditional endothelial NOX5 knock-in mouse. NOX5 increased cyclooxygenase-2 isoform (COX-2) expression and prostaglandin E-2 (PGE(2)) production through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) in TeloHAEC. Protein kinase C (PKC) activation and intracellular calcium level (Ca++) mobilization increased ROS production and NOX5 overexpression, which promoted a COX-2/PGE(2) response in vitro. In the chronic infarction model, mice encoding endothelial NOX5 enhanced the cardiac mRNA expression of COX-2 and PGES, suggesting a COX-2/PGE(2) response to NOX5 presence in an ischemic situation. Our data support that NOX5-derived ROS may modulate the COX-2/PGE(2) axis in endothelial cells, which might play a relevant role in the pathophysiology of heart infarction.
Autores: Solas, Maite; Pejenaute, Álvaro; et al.
ISSN 0891-5849  Vol. 139  Nº S1  2019  págs. S17 - S17
Autores: Varela-Guruceaga M; Milagro FI; Martínez, JA; et al.
ISSN 0303-7207  Vol. 473  2018  págs. 257 - 267
Obesity is characterized by hypertrophy and hyperplasia of adipose tissue, which have been related to the development of hypoxia and insulin resistance. On the other hand, caveolin-1 (Cav-1), one of the main proteins of caveolae, promotes insulin receptor (IR) phosphorylation and the subsequent activation of insulin signaling. In this work we investigated the effect of hypoxia on Cav-1 regulation and the status of insulin signaling in 3T3-L1 adipocytes. Our results showed that hypoxia inhibited adipogenesis and insulin signaling in adipocytes. Furthermore, 48¿h of hypoxia reduced insulin-induced glucose uptake while increased basal glucose uptake. This result was consistent with the upregulation of glucose transporter GLUT1 and the downregulation of GLUT4, which also showed defective translocation to plasma membrane when adipocytes were stimulated with insulin. In addition, the expression of caveolae-related proteins was reduced by hypoxia and chromatin immunoprecipitation assay demonstrated that Cav-1 transcription was directly regulated by HIF-1. These results strengthen the role of caveolae in insulin signaling and help to explain adipocyte response to hypoxia.
Autores: Pejenaute, Álvaro; Ansorena, Eduardo; et al.
ISSN 0891-5849  Vol. 120  Nº Supl. 1  2018  págs. S101 - S101
Autores: Varela-Guruceaga M; Martínez, JA; et al.
ISSN 2162-3945  Vol. 5  Nº 1  2016  págs. 65 - 80
Adipocytes exposed to high glucose concentrations exhibit impaired metabolic function, including an increase of oxidative and proinflammatory factors that might favor the development of insulin resistance. Caveolin-1 (Cav-1) is a key mediator of the insulin transduction pathway whose expression is significantly enhanced during adipocyte differentiation. In this work, we studied the effects of high glucose concentration on the regulation of Cav-1 expression and activation and its relation to the insulin signaling pathway during the adipogenic process and in long-term differentiated adipocytes. Both, long-term high glucose exposure during adipogenesis and short-term glucose incubation of mature adipocytes, promoted triglyceride accumulation in 3T3-L1 cells. The short-term exposure of mature adipocytes to high glucose significantly reduced the sensitivity to insulin of Cav-1, insulin receptor (IR) and potein kinase B (AKT-2) phosphorylation, as well as insulin-induced deoxyglucose uptake. Adipocytes differentiated in the presence of high glucose lost Cav-1 and IR response to insulin-stimulated phosphorylation, but maintained the insulin sensitivity of AKT-2 phosphorylation and deoxyglucose uptake. Although long-term high glucose exposure increased DNA methylation in Cav-1 promoter, Cav-1 expression was not affected. Moreover, these cells showed an increase of Cav-1, IR and AKT-2 protein content, pointing to an adaptive response induced by the long-term high glucose exposure.
Autores: Varela-Guruceaga M; Algarabel, M.; et al.
ISSN 1015-8987  Vol. 36  Nº 4  2015  págs. 1499 - 1516
BACKGROUND/AIMS: Tumor necrosis factor-¿ (TNF-¿)-mediated chronic low-grade inflammation of adipose tissue is associated with obesity and insulin resistance. Caveolin-1 (Cav-1) is the central component of adipocyte caveolae and has an essential role in the regulation of insulin signaling. The effects of TNF-¿ on Cav-1 expression and insulin signaling during adipocyte differentiation and in mature adipocytes were studied. METHODS: 3T3-L1 cells were differentiated (21 days) in the presence TNF-¿ (10 ng/mL) and mature adipocytes were also treated with TNF-¿ for 48 hours. Cav-1 and insulin receptor (IR) gene methylation were determined as well as Cav-1, IR, PKB/AKT-2 and Glut-4 expression and activation by real time RT-PCR and western blot. Baseline and insulin-induced glucose uptake was measured by the 2-[C14]-deoxyglucose uptake assay. RESULTS: TNF-¿ slowed down the differentiation program, hindering the expression of some insulin signaling intermediates without fully eliminating insulin-mediated glucose uptake. In mature adipocytes, TNF-¿ did not compromise lipid-storage capacity, but downregulated the expression of the insulin signaling intermediates, totally blocking insulin-mediated glucose uptake. Insulin sensitivity correlated with the level of activated phospho-Cav-1 in both situations, strongly suggesting the direct contribution of Cav-1 to the maintenance of this physiological response. CONCLUSION: Cav-1 activation by phosphorylation seems to be essential for the maintenance of an active and insulin-sensitive glucose uptake.
Autores: Varela-Guruceaga, M.; Milagro FI; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 9  Nº 4  2014  págs. e95100
Caveolin 1 (Cav-1) is an essential constituent of adipocyte caveolae which binds the beta subunit of the insulin receptor (IR) and is implicated in the regulation of insulin signaling. We have found that, during adipocyte differentiation of 3T3-L1 cells the promoter, exon 1 and first intron of the Cav-1 gene undergo a demethylation process that is accompanied by a strong induction of Cav-1 expression, indicating that epigenetic mechanisms must have a pivotal role in this differentiation process. Furthermore, IR, PKB-Akt and Glut-4 expression are also increased during the differentiation process suggesting a coordinated regulation with Cav-1. Activation of Cav-1 protein by phosphorylation arises during the differentiation process, yet in fully mature adipocytes insulin is no longer able to significantly increase Cav-1 phosphorylation. However, these long-term differentiated cells are still able to respond adequately to insulin, increasing IR and PKB-Akt phosphorylation and glucose uptake. The activation of Cav-1 during the adipocyte differentiation process could facilitate the maintenance of insulin sensitivity by these fully mature adipocytes isolated from additional external stimuli. However, under the influence of physiological conditions associated to obesity, such as chronic inflammation and hypoxia, insulin sensitivity would finally be compromised.
Autores: Varela-Guruceaga, M.; de Miguel, C; et al.
ISSN 1467-7881  Vol. 15  Nº Suppl. 2  2014  págs. 40
Autores: Milagro FI; Mansego, M. L.; de Miguel, C; et al.
ISSN 0098-2997  Vol. 34  Nº 4  2013  págs. 782 - 812
Nutritional factors play a life-long role in human health. Indeed, there is growing evidence that one of the mechanisms by which nutrients and bioactive compounds affect metabolic traits is epigenetics. Complex interactions among food components and histone modifications, DNA methylation, non-coding RNA expression and chromatin remodeling factors lead to a dynamic regulation of gene expression that controls the cellular phenotype. Although perinatal period is the time of highest phenotypic plasticity, contributing largely to developmental programming, also during adulthood there is evidence about a nutritional influence on epigenetic regulation. Similarly to type 2 diabetes, hypertension, atherosclerosis and other metabolic disorders, obesity predisposition and weight loss outcomes have been repeatedly associated to changes in epigenetic patterns. Different non-nutritional risk factors that usually accompany obesity seem also to be involved in these epigenetic modifications, especially hyperglycemia, inflammation, hypoxia and oxidative stress. There are currently three major objectives in epigenetic research in relation to obesity: to search for epigenetic biomarkers to predict future health problems or detect the individuals at most risk, to understand the obesity-related environmental factors that could modulate gene expression by affecting epigenetic mechanisms, and to study novel therapeutic strategies based on nutritional or pharmacological agents that can modify epigenetic marks. At this level, the major tasks are: development of robust epigenetic biomarkers of weight regulation, description of those epigenetic marks more susceptible to be modified by dietary exposures, identification of the active ingredients (and the doses) that alter the epigenome, assessment of the real importance of other obesity-related factors on epigenetic regulation, determination of the period of life in which best results are obtained, and understanding the importance of the inheritance of these epigenetic marks.
Autores: Varela, M.; Milagro FI; et al.
ISSN 0250-6807  Vol. 63  Nº Suppl. 1  2013  págs. 378
Autores: Varela M; de Miguel, C; et al.
ISSN 1661-6499  Vol. 6  2013  págs. 237
Autores: Varela, M.; Milagro FI; et al.
ISSN 1742-464X  Vol. 279  Nº S1  2012  págs. 397 - 397
Autores: Milagro FI; Martínez, JA; et al.
ISSN 1662-4025  Vol. 5  Nº Suppl. 1  2012  págs. 173
Autores: Milagro FI; Campión, Francisco Javier; et al.
Revista: Lipids in Health and Disease
ISSN 1476-511X  Vol. 10  Nº 1  2011  págs. 55
Autores: Milagro FI; Campión, Francisco Javier; et al.
ISSN 0021-9541  Vol. 225  Nº 1  2010  págs. 206 - 213