Role of platelet-derived growth factor c on endothelial dysfunction in cardiovascular diseases

Loss of endothelial function is a common feature to all cardiovascular diseases (CVDs). One of the risk factors associated with the development of CVDs is the hyperglycaemia that occurs in patients with metabolic disorders such as Type 1 and Type 2 diabetes mellitus. Hyperglycaemia causes endothelial dysfunction through increased production of reactive oxygen species (ROS) from different cellular sources leading to oxidative stress. Vascular endothelial growth factor (VEGF) is essential in the stimulation and maintenance of endothelial functional aspects and, although it can mitigate the impact of ROS, VEGF-mediated signalling is partially inhibited in diabetes mellitus. The search for therapeutic strategies that preserve, protect and improve the functions of the endothelium is of great relevance in the investigation of CVDs associated with hyperglycaemia. Platelet-derived growth factor C (PDGF-C) is a peptide with angiogenic properties, independent of VEGF, that stimulates angiogenesis and revascularization of ischemic tissue. In a diabetic mouse model, PDGF-C stimulates mature endothelial cell migration, angiogenesis, endothelial progenitor cell mobilization, and increased neovascularization, and protects blood vessels in a retinal degeneration model activating anti-apoptosis and proliferation signalling pathways in endothelial cells. This review summarizes the information on the damage that high D-glucose causes on endothelial function and the beneficial effects that PDGF-CC could exert in this condition

Moléculas moduladoras de vías de señalización basales y desencadenadas por el Factor de Crecimiento Derivado de Plaquetas (PDGF) en un modelo celular de fibrosarcoma humano

Overexposure of the Platelet Derivative Growth Factor (PDGF) and its receptors has been linked to the development of pathologies associated with the loss of proliferation control, like cancer, mainly soft tissue sarcomas and gliomas. Thus, the development of therapeutic elements that inhibit the biological responses unleashed by these molecules have been a topic of preclinical studies in different types of cancer. In that sense, the objective of this study was to evaluate the effect of peptides synthesized from the natural linking of isoform PDGF-BB and specific intracellular protein inhibitors on the activation of modulators of signaling ways PI3K/Akt y MAPK baseline and dependent on PDGF and on the proliferative phenotype of cellular line HT1080.La sobreexpresión del Factor de Crecimiento Derivado de Plaquetas (PDGF) y sus receptores ha sido relacionada con el desarrollo de patologías asociadas a la pérdida del control de la proliferación, como el cáncer, principalmente sarcomas de tejidos blandos y gliomas. Por lo anterior, el desarrollo de agentes terapéuticos que inhiban las respuestas biológicas desencadenadas por estas moléculas han sido blanco de estudios preclínicos en diferentes tipos de cáncer. En este sentido, el objetivo de este estudió fue evaluar el efecto de dos péptidos sintetizados a partir del ligando natural de la isoforma PDGF-BB, así como de inhibidores específicos de proteínas intracelulares, sobre la activación de moduladores de las vías de señalización PI3K/Akt y MAPK basales y dependientes de PDGF y sobre el fenotipo proliferativo de la línea celular HT1080

Tamoxifen treatment of breast cancer cells: Impact on Hedgehog/GLI1 signaling

The selective estrogen receptor (ER) modulator tamoxifen (TAM) has become the standard therapy for the treatment of ER+ breast cancer patients. Despite the obvious benefits of TAM, a proportion of patients acquire resistance to treatment, and this is a significant clinical problem. Consequently, the identification of possible mechanisms involved in TAM-resistance should help the development of new therapeutic targets. In this study, we present in vitro data using a panel of different breast cancer cell lines and demonstrate the modulatory effect of TAM on cellular proliferation and expression of Hedgehog signaling components, including the terminal effector of the pathway, the transcription factor GLI1. A variable pattern of expression following TAM administration was observed, reflecting the distinctive properties of the ER+ and ER− cell lines analyzed. Remarkably, the TAM-induced increase in the proliferation of the ER+ ZR-75-1 and BT474 cells parallels a sustained upregulation of GLI1 expression and its translocation to the nucleus. These findings, implicating a TAM-GLI1 signaling cross-talk, could ultimately be exploited not only as a means for novel prognostication markers but also in efforts to effectively target breast cancer subtypes

Tamoxifen treatment of breast cancer cells : Impact on Hedgehog/GLI1 signaling

The selective estrogen receptor (ER) modulator tamoxifen (TAM) has become the standard therapy for the treatment of ER+ breast cancer patients. Despite the obvious benefits of TAM, a proportion of patients acquire resistance to treatment, and this is a significant clinical problem. Consequently, the identification of possible mechanisms involved in TAM-resistance should help the development of new therapeutic targets. In this study, we present in vitro data using a panel of different breast cancer cell lines and demonstrate the modulatory effect of TAM on cellular proliferation and expression of Hedgehog signaling components, including the terminal effector of the pathway, the transcription factor GLI1. A variable pattern of expression following TAM administration was observed, reflecting the distinctive properties of the ER+ and ER´ cell lines analyzed. Remarkably, the TAM-induced increase in the proliferation of the ER+ ZR-75-1 and BT474 cells parallels a sustained upregulation of GLI1 expression and its translocation to the nucleus. These findings, implicating a TAM-GLI1 signaling cross-talk, could ultimately be exploited not only as a means for novel prognostication markers but also in efforts to effectively target breast cancer subtypes. © 2016 by the authors; licensee MDPI, Basel, Switzerland

Glycaemia dynamics in gestational diabetes mellitus

Pregnant women may develop gestational diabetes mellitus (GDM), a disease of pregnancy characterised by maternal and fetal hyperglycaemia with hazardous consequences to the mother, the fetus, and the newborn. Maternal hyperglycaemia in GDM results in fetoplacental endothelial dysfunction. GDM-harmful effects result from chronic and short periods of hyperglycaemia. Thus, it is determinant to keep glycaemia within physiological ranges avoiding short but repetitive periods of hyper or hypoglycaemia. The variation of glycaemia over time is defined as 'glycaemia dynamics'. The latter concept regards with a variety of mechanisms and environmental conditions leading to blood glucose handling. In this review we summarized the different metrics for glycaemia dynamics derived from quantitative, plane distribution, amplitude, score values, variability estimation, and time series analysis. The potential application of the derived metrics from self-monitoring of blood glucose (SMBG) and continuous glucose monitoring (CGM) in the potential alterations of pregnancy outcome in GDM are discussed

Exposome and foetoplacental vascular dysfunction in gestational diabetes mellitus

A balanced communication between the mother, placenta and foetus is crucial to reach a successful pregnancy. Several windows of exposure to environmental toxins are present during pregnancy. When the women metabolic status is affected by a disease or environmental toxin, the foetus is impacted and may result in altered development and growth. Gestational diabetes mellitus (GDM) is a disease of pregnancy characterised by abnormal glucose metabolism affecting the mother and foetus. This disease of pregnancy associates with postnatal consequences for the child and the mother. The whole endogenous and exogenous environmental factors is defined as the exposome. Endogenous insults conform to the endo-exposome, and disruptors contained in the immediate environment are the ecto-exposome. Some components of the endo-exposome, such as Selenium, vitamins D and B12, adenosine, and a high-fat diet, and ecto-exposome, such as the heavy metals Arsenic, Mercury, Lead and Copper, and per- and polyfluoroakyl substances, result in adverse pregnancies, including an elevated risk of GDM or gestational diabesity. The impact of the exposome on the human placenta's vascular physiology and function in GDM and gestational diabesity is reviewed

Role of Platelet-Derived Growth Factor C (PDGF-CC) on cellular mechanisms associated with an endothelial dysfunction model induced by high D-glucose concentrations

Las enfermedades cardiovasculares constituyen la primera causa de muerte a nivel mundial. Uno de los factores de riesgo asociados a la aparición de estas enfermedades es el aumento anormal de los niveles de glucosa en plasma (hiperglicemia) que ocurre en pacientes con enfermedades metabólicas como la diabetes mellitus. Una característica común a todas las patologías vasculares es la presencia de un fenotipo endotelial alterado, conocida como disfunción endotelial; en pacientes diabéticos, esta condición ha sido atribuida a las condiciones de resistencia a la insulina e hiperglicemia. La hiperglicemia induce disfunción endotelial por aumento en la producción de especies reactivas de oxígeno citosólicas, y principalmente, en la cadena de transporte de electrones mitocondrial. En este contexto, la búsqueda de moléculas exógenas o endógenas que protejan al endotelio vascular de los efectos dañinos producidos por la hiperglicemia se establece como un campo amplio en investigación para el hallazgo de blancos terapéuticos importantes para el tratamiento de enfermedades cardiovasculares. Publicaciones recientes proponen a PDGF-C como una nueva molécula que ejerce múltiples efectos positivos sobre células endoteliales, principalmente en procesos de angiogénesis e incluso en condiciones de diabetes; sin embargo, sus efectos sobre otros mecanismos asociados a disfunción endotelial no están completamente descritos. Por lo anterior, el objetivo de este estudio fue determinar el efecto de PDGF-C sobre las alteraciones deletéreas inducidas por altos niveles de D-glucosa en células endoteliales, entre los que se incluyeron: estrés oxidativo y evaluación de la expresión del factor de transcripción Nrf-2 involucrado en respuesta antioxidante, modulación de la red mitocondrial asociada a la expresión de proteínas de fusión y fisión, activación de la sintasa de óxido nítrico endotelial y producción de óxido nítrico, producción de endotelina-1 y evaluación de las vías de señalización PI3K/Akt y MAPK asociadas a la producción de este vasodilatador y vasoconstrictor, respectivamente. Los resultados de este estudio indican que PDGF-C redujo la producción de ROS mitocondrial inducida por alta concentración de D-glucosa y que este efecto estuvo asociado al aumento en la expresión y actividad de la enzima antioxidante SOD2; en las mismas condiciones, PDGF-C redujo la expresión relativa del gen Keap1, involucrado en la retención de Nrf2 en el citoplasma. PDGF-C atenuó la fragmentación de la red mitocondrial inducida por alta concentración de D-glucosa, indujo la expresión de la proteína de fusión mitocondrial OPA1 y moduló la fosforilación de los residuos Ser616 y Ser637 de la proteína de fisión DRP1, conocidos por promover y atenuar la fisión mitocondrial, respectivamente. PDGF-C indujo la activación de eNOS por fosforilación del residuo Ser1177; sin embargo, no se observó fosforilación de Akt ni producción de NO inducida por PDGF-C. PDGF-C moduló la fosforilación de las proteínas ERK1/2 y disminuyó los niveles de ET-1, producidos en condiciones de alta D-glucosa. Estos resultados sugieren que PDGF-C puede ser considerado un blanco terapéutico prometedor en patologías cardiovasculares asociadas a patologías metabólicas como la diabetes mellitus, ya que ejerce un papel reparador sobre los efectos deletéreos que altas concentraciones de glucosa inducen sobre el endotelio vascular.ColcienciasPontificia Universidad JaverianaCentro de Estudios Interdisciplinarios Básicos y Aplicados (CeIBA)Cardiovascular diseases are considered the first cause of death worldwide. One risk factor associated with the onset of these diseases is the abnormal increase in plasma glucose levels (hyperglycemia) seen in patients with metabolic diseases such as diabetes mellitus. A common characteristic of all vascular pathologies is the existence of an altered phenotype, known as endothelial dysfunction. In diabetic patients, this condition has been linked to insulin resistance and hyperglycemia. Hyperglycemia induces endothelial dysfunction due to the increase in reactive oxygen species production from the cytosol and mainly from the mitochondrial electron transport chain. In this context, searching for exogenous and endogenous molecules that protect the vascular endothelium is a wide field of research for discovering of critical therapeutic targets for cardiovascular disease treatment. Recent publications propose PDGF-C as a new molecule that exerts multiple positive effects on endothelial cells, mainly in angiogenesis, even in diabetes conditions. However, its impact on other mechanisms associated with endothelial dysfunction is not entirely described. Due to the above points, the purpose of this study was to determine the effect of PDGF-C on deleterious alterations induced by high D-glucose levels on endothelial cells, including oxidative stress and Nrf-2 transcription factor expression, mitochondrial network modulation and fusion and fission proteins expression, nitric oxide synthase activation and nitric oxide production, endothelin-1 production, and evaluation of PI3K/Akt and MAPK signaling pathways. Results from this study show that PDGF-C reduced mitochondrial ROS production induced by high D-glucose, and this effect was associated with the increased expression of the antioxidant enzyme SOD2; in the same conditions, PDGF-C modulated the Keap1 gene expression, involved in the Nrf2 retention in the cytoplasm. PDGF-C also attenuated the mitochondrial network fragmentation induced by high D-glucose, induced the expression of the mitochondrial fusion protein OPA1, and modulated the phosphorylation of DRP1 Fission proteins on Ser616 and Ser637 residues, known as by promoting and attenuating the mitochondrial fission, respectively. PDGF-C induced the eNOS activation by phosphorylation of Ser1177 residue; however, phosphorylation of Akt and increased NO production were not induced by PDGF-C. On the other hand, PDGF-C modulated the phosphorylation of ERK1/2 and reduced the ET-1 levels raised by high D-glucose. These results suggest that PDGF-C could be considered a therapeutic target for cardiovascular pathologies such as diabetes mellitus because of its repairing role on the dangerous effects that high glucose induces on the vascular endothelium.Doctor en Ciencias BiológicasDoctoradohttps://orcid.org/my-orcid?orcid=0000-0002-9225-341

Role of platelet-derived growth factor c on endothelial dysfunction in cardiovascular diseases

Loss of endothelial function is a common feature to all cardiovascular diseases (CVDs). One of the risk factors associated with the development of CVDs is the hyperglycaemia that occurs in patients with metabolic disorders such as Type 1 and Type 2 diabetes mellitus. Hyperglycaemia causes endothelial dysfunction through increased production of reactive oxygen species (ROS) from different cellular sources leading to oxidative stress. Vascular endothelial growth factor (VEGF) is essential in the stimulation and maintenance of endothelial functional aspects and, although it can mitigate the impact of ROS, VEGF-mediated signalling is partially inhibited in diabetes mellitus. The search for therapeutic strategies that preserve, protect and improve the functions of the endothelium is of great relevance in the investigation of CVDs associated with hyperglycaemia. Platelet-derived growth factor C (PDGF-C) is a peptide with angiogenic properties, independent of VEGF, that stimulates angiogenesis and revascularization of ischemic tissue. In a diabetic mouse model, PDGF-C stimulates mature endothelial cell migration, angiogenesis, endothelial progenitor cell mobilization, and increased neovascularization, and protects blood vessels in a retinal degeneration model activating anti-apoptosis and proliferation signalling pathways in endothelial cells. This review summarizes the information on the damage that high D-glucose causes on endothelial function and the beneficial effects that PDGF-CC could exert in this condition

Tendencia Editorial UR Número 35

En ese boletín, se ha tomado la decisión de invitar a algunos representantes de bibliotecas, investigadores y personas destacadas en el mundo del libro para que nos cuenten, desde sus experiencias, cómo entienden el libro como producto, como materialidad y como representatividad. Con el boletín buscamos mostrar diversas perspectivas y aristas, ver al libro como un ente vivo que tiene diferentes dinámicas que lo configuran como un objeto con múltiples cargas históricas, de conocimiento, propósitos, políticas, estéticas.In this bulletin, the decision has been made to invite some representatives of libraries, researchers and prominent people in the book world to tell us, based on their experiences, how they understand the book as a product, as materiality and as representativeness. With the newsletter we seek to show different perspectives and edges, to see the book as a living entity that has different dynamics that configure it as an object with multiple historical charges, knowledge, purposes, politics, aesthetics