Aldosterone/MR Signaling, Oxidative Stress, and Vascular Dysfunction

The mineralocorticoid receptor (MR) is a transcription factor of the family of steroid receptors that classically binds the hormone aldosterone. The contribution of MR in the regulation of sodium retention and blood pressure is well known. However, MR is expressed in extrarenal tissues including endothelial and vascular smooth muscle cells, and its activation leads to vascular remodeling, vascular stiffness, and endothelial dysfunction leading to vascular damage, an important pathophysiological process in hypertension and other cardiovascular diseases. Moreover, MR is expressed in nonvascular cells in close contact with the vascular wall including immune cells and adipocytes that might influence vascular function and structure. MR activation involves its translocation to the nucleus and regulation of gene transcription. In addition, aldosterone exerts rapid non-genomic effects mediated by MR-dependent and MR-independent mechanisms. Both genomic and non-genomic effects facilitate reactive oxygen species (ROS) production (particularly by the enzyme NADPH oxidase), inflammation, and fibrosis, which, in turn, promote tissue remodeling, vascular stiffening, and endothelial dysfunction. Studies with MR antagonists and experimental models with cell-specific knockout or overexpression of MR further support a role for aldosterone/MR-mediated oxidative stress-dependent processes in vascular damage. This review focuses on the relationship between aldosterone/MR signaling and oxidative stress and the implications in vascular regulation in health and disease

Vascular lysyl oxidase over-expression alters extracellular matrix structure and induces oxidative stress

Lysyl oxidase (LOX) participates in the assembly of collagen and elastin fibres. The impact of vascular LOX over-expression on extracellular matrix (ECM) structure and its contribution to oxidative stress has been analysed. Methods Studies were conducted on mice over-expressing LOX (Tg), specifically in smooth muscle cells (VSMC). Gene expression was assessed by real-time PCR analysis. Sirius Red staining, H 2 O 2 production and NADPH oxidase activity were analysed in different vascular beds. The size and number of fenestra of the internal elastic lamina were determined by confocal microscopy. Results LOX activity was up-regulated in VSMC of transgenic mice compared with cells from control animals. At the same time, transgenic cells deposited more organised elastin fibres and their supernatants induced a stronger collagen assembly in in vitro assays. Vascular collagen cross-linking was also higher in Tg mice, which showed a decrease in the size of fenestrae and an enhanced expression of Fibulin-5. Interestingly, higher H 2 O 2 production and NADPH oxidase activity was detected in the vascular wall from transgenic mice. The H 2 O 2 scavenger catalase attenuated the stronger deposition of mature elastin fibres induced by LOX transgenesis. Conclusions LOX over-expression in VSMC was associated with a change in the structure of collagen and elastin fibres. LOX could constitute a novel source of oxidative stress that might participate in elastin changes and contribute to vascular remodellingLa lisil oxidasa (LOX) contribuye al ensamblaje de las fibras de colágeno y elastina de la matriz extracelular (MEC). Hemos determinado las consecuencias de la sobre-expresión vascular de LOX sobre la estructura de la MEC y su contribución al estrés oxidativo. Métodos: Los estudios se desarrollaron en ratones que sobre-expresan la LOX (Tg) específicamente en células musculares lisas vasculares (CMLV). Se realizaron análisis por PCR a tiempo real, tinción de rojo sirio, producción de H2O2 y actividad NADPH oxidasa. Se caracterizaron las fenestras de la lámina elástica interna mediante microscopía confocal. Resultados: Las CMLV de ratones transgénicos presentaron niveles de actividad LOX superiores a los de animales control. En consonancia, las células transgénicas depositaron más fibras de elastina organizada y sus sobrenadantes indujeron un mayor ensamblaje de colágeno en ensayos in vitro. El nivel de colágeno maduro fue superior en la pared vascular de ratones Tg, que presentaban un menor área de las fenestras y un aumento de la expresión de la Fibulina-5. La producción vascular de H2O2 y la actividad NADPH oxidasa fueron superiores en los ratones transgénicos. La incubación de CMLV con catalasa atenuó el incremento en la deposición de fibras de elastina madura inducido por la transgénesis de LOX. Conclusiones: La sobre-expresión de la LOX en CMLV se asocia a una alteración de la estructura vascular del colágeno y la elastina. La LOX podría constituir una nueva fuente de estrés oxidativo que participaría en la alteración estructural de la MEC y podría contribuir al remodelado vascularEste estudio se ha financiado por la Fundación Española de Aterosclerosis, Beca SEA/FEA de Investigación básica 2016 y por el Ministerio de Economía y Competitividad (MINECO)-Instituto de Salud Carlos III (ISCIII) [proyectos PI15/01016, PI13/01488, SAF2012-36400; SAF2015-64767-R]. El CIBER de Enfermedades Cardiovasculares es una iniciativa del ISCIII. AMB recibió una ayuda del programa Ramón y Cajal (RYC-2010-06473). El estudio ha sido cofinanciado por el Fondo Europeo de Desarrollo Regional (FEDER

Differential renal effects of candesartan at high-and ultra-high doses in diabetic mice: potential role of ACE2/AT2R/Mas

High doses of Ang II receptor (AT1R) blockers (ARBs) are renoprotective in diabetes. Underlying mechanisms remain unclear. We evaluated whether high/ultra-high doses of candesartan (ARB) up-regulate angiotensin-converting enzyme 2 (ACE2)/Ang II type 2 receptor (AT2R)/Mas receptor [protective axis of the of the renin–angiotensin system (RAS)] in diabetic mice. Systolic blood pressure (SBP), albuminuria and expression/activity of RAS components were assessed in diabetic db/db and control db/+ mice treated with increasing candesartan doses (intermediate, 1 mg/kg/d; high, 5 mg/kg/d; ultra-high, 25 and 75 mg/kg/d; 4 weeks). Lower doses candesartan did not influence SBP, but ultra-high doses reduced SBP in both groups. Plasma glucose and albuminuria were increased in db/db compared with db/+ mice. In diabetic mice treated with intermediate dose candesartan, renal tubular damage and albuminuria were ameliorated and expression of ACE2, AT2R and Mas and activity of ACE2 were increased, effects associated with reduced ERK1/2 phosphorylation, decreased fibrosis and renal protection. Ultra-high doses did not influence the ACE2/AT2R/Mas axis and promoted renal injury with increased renal ERK1/2 activation and exaggerated fibronectin expression in db/db mice. Our study demonstrates dose-related effects of candesartan in diabetic nephropathy: intermediate–high dose candesartan is renoprotective, whereas ultra-high dose candesartan induces renal damage. Molecular processes associated with these effects involve differential modulation of the ACE2/AT2R/Mas axis: intermediate–high dose candesartan up-regulating RAS protective components and attenuating pro-fibrotic processes, and ultra-high doses having opposite effects. These findings suggest novel mechanisms through the protective RAS axis, whereby candesartan may ameliorate diabetic nephropathy. Our findings also highlight potential injurious renal effects of ultra-high dose candesartan in diabetes

A New Hydrogen Sensor Based on a Pt/GaAs Schottky Diode

4 páginas, 7 figuras, 1 tabla.-- PACS: 82.45.Jn; 07.07.Df; 85.30.Hi.A new hydrogen-sensitive detector based on a Pt/GaAs Schottky diode has been fabricated. The devices have beencharacterized by dark current-voltage and capacitance-voltage measurements, as a function of temperature and gas phasecomposition. At 150°C, the detection limit for hydrogen is 6 ppm in a nitrogen environment and 200 ppm in air.Peer reviewe

C-Src, ERK1/2 and Rho kinasemediate hydrogen peroxide-induced vascular contraction in hypertension: Role ofTXA2, NAD(P)H oxidase andmitochondria

AIM: : The aim of this study was to analyse the signalling pathways involved in H2O2 vascular responses in hypertension. METHODS: Vascular function, thromboxane A2 (TXA2) production, oxidative stress and protein expression were determined in mesenteric resistance arteries (MRAs) from hypertensive (spontaneously hypertensive rats, SHR) and normotensive Wistar Kyoto (WKY) rats. RESULTS: H2O2 and the TP agonist U46619 induced greater contractile responses in MRA from SHR than WKY. Moreover, H2O2 increased TXA2 production more in SHR than in WKY. The c-Src inhibitor PP1 reduced H2O2 and U46619-induced contraction and TXA2 release in both strains. The ERK1/2 inhibitor PD98059 reduced H2O2 but not U46619-induced contraction only in SHR arteries. The Rho kinase inhibitor Y26372 reduced H2O2 and U46619-induced contractions only in SHR arteries. Basal c-Src, ERK1/2 and Rho kinase expression were greater in MRA from SHR than WKY. In SHR, the combination of PD98059 with the TP antagonist SQ29548 but not with Y27632 inhibited the H2O2 contraction more than each inhibitor alone. H2O2 and U46619 increased NAD(P)H oxidase activity and O2 production and decreased mitochondrial membrane potential in vessels from SHR. The effects induced by H2O2 were abolished by inhibitors of TXA2 synthase, ERK1/2 and c-Src. The mitochondrial antioxidant mitoTEMPO reduced H2O2-induced contraction and NAD(P)H oxidase activation. CONCLUSION: In arteries from WKY, c-Src mediates H2O2 contractile responses by modulating TXA2 release and TXA2 effect. In SHR, H2O2 induces c-Src dependent TXA2 release that provokes vascular contractile responses through Rho kinase, c-Src and O2 from NAD(P)H Oxidase and mitochondria. Moreover, ERK1/2 activation contributes to H2O2 contraction in SHR through effects on mitochondria/NAD(P)H Oxidase

Respuesta

Lo estimulante de ambos comentarios es que nos invitan a ir más allá de los propósitos que nos habíamos fijado. Originalmente nos interesaba problematizar la correspondencia entre impulsos localizadores o globalizadores y posiciones de poder, para proponer que al menos en ciertos escenarios transnacionalizados la disputa política por la fijación de sentidos distingue a las partes enfrentadas no tanto por determinaciones supuestamente divergentes a globalizar (posición hcgcmónica) o localizar (posición subalterna), sino más bien poruña disputa centrada en qué y cómo globalizar y/o localizar. Obviamente, tal disputa no está al margen de que la dinámica de poder que entrama esos escenarios signe diferencialmente la suerte de lo que en concreto se globalice o localice.Respuesta sobre los comentarios realizados respecto del artículo de Briones, Claudia ...[et. al.]: “Desinflando el globo: otras caras de la globalización”. Relaciones de la Sociedad Argentina de Antropología, XXI, 1996, pp. 119-136.Sociedad Argentina de Antropologí

Respuesta

Lo estimulante de ambos comentarios es que nos invitan a ir más allá de los propósitos que nos habíamos fijado. Originalmente nos interesaba problematizar la correspondencia entre impulsos localizadores o globalizadores y posiciones de poder, para proponer que al menos en ciertos escenarios transnacionalizados la disputa política por la fijación de sentidos distingue a las partes enfrentadas no tanto por determinaciones supuestamente divergentes a globalizar (posición hcgcmónica) o localizar (posición subalterna), sino más bien poruña disputa centrada en qué y cómo globalizar y/o localizar. Obviamente, tal disputa no está al margen de que la dinámica de poder que entrama esos escenarios signe diferencialmente la suerte de lo que en concreto se globalice o localice.Respuesta sobre los comentarios realizados respecto del artículo de Briones, Claudia ...[et. al.]: “Desinflando el globo: otras caras de la globalización”. Relaciones de la Sociedad Argentina de Antropología, XXI, 1996, pp. 119-136.Sociedad Argentina de Antropologí

G protein-coupled receptor kinase 2 (GRK2) as a potential therapeutic target in cardiovascular and metabolic diseases

G protein-coupled receptor kinase 2 (GRK2) is a central signaling node involved in the modulation of many G protein-coupled receptors (GPCRs) and also displaying regulatory functions in other cell signaling routes. GRK2 levels and activity have been reported to be enhanced in patients or in preclinical models of several relevant pathological situations, such as heart failure, cardiac hypertrophy, hypertension, obesity and insulin resistance conditions, or non-alcoholic fatty liver disease (NAFLD), and to contribute to disease progression by a variety of mechanisms related to its multifunctional roles. Therefore, targeting GRK2 by different strategies emerges as a potentially relevant approach to treat cardiovascular disease, obesity, type 2 diabetes, or NAFLD, pathological conditions which are frequently interconnected and present as co-morbidities.Our laboratories are supported by Ministerio de Economía; Industria y Competitividad (MINECO) of Spain (grant SAF2017- 84125-R to FM and CM and SAF2016-80305-P to MS and AMB), CIBERCV-Instituto de Salud Carlos III, Spain (grants CB16/11/00278 and CB16/11/00286 to FM and MS, respectively, co-funded with European FEDER contribution), and Programa de Actividades en Biomedicina de la Comunidad de Madrid (grants B2017/BMD-3671-INFLAMUNE to FM and B2017/ BMD-3676-AORTASANA to MS)

Desinflando el globo: otras caras de la globalización

En los últimos años, la globalización aparece en las Ciencias Sociales como un significante con al menos dos significados. Por un lado, remite a un proceso de destcrritorialización de la economía y de ciertos discursos político-culturales asociados. Por el otro, circunscribe como concepto procesos de construcción de hegemonía en un contexto deflexibilización del capitalismo. En este último sentido, la idea de localización surge progresivamente como herramienta para identificar discursos heterogeneizadores, vistos como contracara de tendencias opuestas enfatizadas por la noción de globalización. En este ensayo, nos proponemos revisar algunos supuestos que hacen problemática la dupla globalización/localización. Fundamentalmente el de la correspondencia lineal entre sectores sociales y tendencias excluyentes de uno u otro signo. Para ilustrar nuestra perspectiva comparamos formas posibles de globalización promovidas desde grupos indígenas y religiosos. Por ultimo, presentamos una reflexión critica sobre algunos abordajes de la noción de cultura en contextos de glohalizacion.Over the last several yeros, globalization appears in social sciences as a significara with at least two meanings. On one hand, it refers to a process of dcterritorialization ofthe economy associatedwith certainpolitical-cultural discourses. On the other, it circunscribes as concepts, processes of construction ofhegemony in a contexto/capitalismflexibilization. In the lastsense, the idea oflocalization arises progesssively as a tool to identify heterogeneous discourses, in contrast to opposing tendencies emphasized by the notion of globaüzation. In this essay, we review some assumptions which make the doble concept localizationl globalization troublesome. Essentially, the lineal correspondance between social sections and exduding tendencies ofboth concepts. In order to ülustrate our perspective, we compared possible ways of globalization promotedfrom indigenous and religious groups. Lastly, wepresent a criücal reflexión on some approaches to the notion of culture in globalization contexts.Sociedad Argentina de Antropologí

Molecular physiopathology of obesity-related diseases: multi-organ integration by GRK2

Obesity is a worldwide problem that has reached epidemic proportions both in developed and developing countries. The excessive accumulation of fat poses a risk to health since it favours the development of metabolic alterations including insulin resistance and tissue inflammation, which further contribute to the progress of the complex pathological scenario observed in the obese. In this review we put together the different outcomes of fat accumulation and insulin resistance in the main insulin-responsive tissues, and discuss the role of some of the key molecular routes that control disease progression both in an organ-specific and also in a more systemic manner. Particularly, we focus on the importance of studying the integrated regulation of different organs and pathways that contribute to the global pathophysiology of this condition with a specific emphasis on the role of emerging key molecular nodes such as the G protein-coupled receptor kinase 2 (GRK2) signalling hubMinisterio Sanidad y Consumo-Instituto de Salud Carlos III, Spain; Grants SAF2014-55511-R and SAF2012-36400 from Ministerio de Economia y Competitividad (MINECO), Spain (to FM-CM and MS); S2010/BMD-2332 (INDISNET) from Comunidad de Madrid, Spain (to FM); an EFSDNovo Nordisk Grant (to FM) and Fundacion Ramon Areces (to CM and AMB)Peer Reviewe