N. de las Heras

Factors involved in rosuvastatin induction of insulin sensitization in rats fed a high fat diet.

BACKGROUND AND AIM To investigate whether rosuvastatin can improve insulin sensitivity in overweight rats having a high fat diet (HFD). The potential mechanisms involved in this action were evaluated, including SIRT-1, other factors involved in glucose metabolism and stress signaling pathways. METHODS AND RESULTS Male Wistar rats (n = 30) were divided into three groups: (i) rats fed a standard diet (3.5% fat); (ii) rats fed a HFD (33.5% fat); and (iii) rats fed a HFD and treated with rosuvastatin (15 mg/kg/day). Evolution: 7 weeks. HFD rats showed increased body, epididymal and lumbar adipose tissue weights. Plasma levels of cholesterol, triglycerides, VLDL, glucose and insulin and leptin/adiponectin ratio were higher in HFD rats, and rosuvastatin treatment reduced them. SIRT-1, p53, PGC-1α, PPAR-γ and GLUT-4 protein levels in white adipose tissue (WAT) were lower, and JNK was higher in HFD rats compared to controls. Rosuvastatin treatment normalized expression of these mediators. Endothelium-dependent relaxation was reduced in mesenteric rings from HFD rats compared to controls and rosuvastatin enhanced it in HFD rats. CONCLUSION Rosuvastatin treatment reduced insulin resistance without affecting body weight or WAT loss in HFD rats. Reduction of leptin and JNK, and enhancement of SIRT-1, p53, PGC-1α, PPAR-γ and GLUT-4 expression in WAT could contribute to insulin sensitization. Normalization of SIRT-1 expression in WAT could be considered a key novel mechanism that aids in explaining the beneficial effects of rosuvastatin on the amelioration of glucose metabolism and the arrangement of multiple signaling pathways participating in insulin resistance in overweight HFD rats.

Relevance of vascular peroxisome proliferator-activated receptor γ coactivator-1α to molecular alterations in atherosclerosis.

•  What is the central question of this study? Does PGC‐1α play a key role in vascular alterations induced by cholesterol+coconut oil diet in rabbits? •  What is the main finding and its importance? Vascular expression of PGC‐1α, SIRT1 and PPARγ were reduced in atherosclerotic rabbits. Furthermore, PGC‐1α correlated with processes involved in atherosclerosis (endothelial dysfunction, oxidative stress and inflammation). Reduction of PGC‐1α seems to play an important role in the molecular alterations during the development of atherosclerosis.

Metabolic differences between white and brown fat from fasting rabbits at physiological temperature

It has been suggested that activated brown adipose tissue (BAT) shows increased glucose metabolic activity. However, less is known about metabolic activity of BAT under conditions of fasting and normal temperature. The aim of this study was to compare the possible differences in energetic metabolism between BAT and white adipose tissue (WAT) obtained from rabbits under the conditions of physiological temperature and 24 h after fasting conditions. The study was carried out on New Zealand rabbits (n=10) maintained for a period of 8 weeks at 23±2 °C. Food was removed 24 h before BAT and WAT were obtained. Protein expression levels of the glycolytic-related protein, glyceraldehyde-3-phosphate dehydrogenase, and pyruvate dehydrogenase were higher in WAT than that in BAT. The expression level of carnitine palmitoyltransferase 1 (CPT1) and CPT2, two fatty acid mitochondrial transporters, and the fatty acid β-oxidation-related enzyme, acyl CoA dehydrogenase, was higher in BAT than in WAT. Cytosolic malate dehydrogenase expression and malate dehydrogenase activity were higher in WAT than in BAT. However, lactate dehydrogenase expression and lactate content were significantly higher in BAT than in WAT. In summary, this study for the first time, to our knowledge, has described how under fasting and normal temperature conditions rabbit BAT seems to use anaerobic metabolism to provide energetic fuel, as opposed to WAT, where the malate-aspartate shuttle and, therefore, the gluconeogenic pathway seem to be potentiated.

Efectos de las estatinas sobre la presión arterial

Resumen Las estatinas han demostrado claramente su capacidad para disminuir la morbimortalidad cardiovascular debido principalmente a sus efectos sobre el colesterol serico y las LDL, ademas de la estabilizacion de la placa y la reduccion del riesgo trombotico. Sin embargo, en los ultimos anos diversos estudios indican que las estatinas tienen ademas efectos sobre la PA y la proteccion de organos diana. Estos efectos pueden ser en parte dependientes de la reduccion de la colesterolemia, pero otros mecanismos distintos a este parecen intervenir en los efectos antihipertensivos de las estatinas. Entre ellos sus acciones sobre el manejo renal de sodio, la respuesta constrictora a diversos agentes, el remodelado vascular y diversas acciones sobre factores vasoactivos derivados del endotelio y el sistema renina angiotensina.

BRCA2 gene mutations and coagulation-associated biomarkers

Thromboembolic events are the second cause of death in cancer patients, although the mechanisms underlying this increased thromboembolic risk remain unclear. The aims of this study were to examine whether BRCA2 gene mutations may modify the circulating levels of thrombocoagulation biomarkers and whether breast cancer development may influence changes in such circulating biomarkers. The study was performed in 25 women with mutations in the BRCA2 gene (n=12 breast cancer, n=13 breast cancer-free) and in 13 BRCA2 non-mutant controls. Results revealed that plasma levels of fibrinogen gamma chain isotypes 2 and 3, haptoglobin isotypes 4 and 5, serotransferrin isotypes 3 and 4 and convertase C3/C5 isotypes 4 and 5 were significantly higher in BRCA2 mutation carriers compared to controls. However, plasma levels of vitamin D binding protein isotype 1 and alpha1-antitrypsin isotypes 2, 3 and 4 were significantly decreased in BRCA2 mutation carriers compared to controls. Plasma expression of PF4 and P-selectin was significantly higher in BRCA2 mutations carriers than in controls. BRCA2 truncated mutations conserving a binding region for RAD51 were associated with increased plasma levels of alpha1-antitrypsin isotypes 3 and 4 with respect to women showing BRCA2 mutations that loss the binding RD51 region to BRCA2. Only plasma levels of vitamin D binding protein isotypes 1 and 3 were significantly reduced and alpha 1-antitrypsin isotype 1 was increased in cancer-free BRCA2 mutation carriers compared to BRCA2 mutation carriers with breast cancer. The presence of BRCA2 mutations is associated with increased plasma levels of thrombo-coagulating-related proteins, which are independent to breast cancer development.

Angiotensina II e hipertensión arterial: consecuencias del antagonismo de sus receptores

La angiotensina II (AII) es uno de los principales factores vasoactivos implicados en el desarrollo y las complicaciones de diversas patologias cardiovasculares y renales como la hipertension arterial, la insuficiencia cardiaca, la insuficiencia renal, la nefropatia diabetica, etc.. Por ello, la inhibicion de las acciones de la AII ha sido y continua siendo de los objetivos primordiales de la terapeutica cardiovascular. Los inhibidores de la enzima de conversion de la angiotensina (IECA) han demostrado una gran eficacia en el tratamiento de las alteraciones cardiovasculares anteriormente mencionadas. La busqueda de formas de inhibicion de las acciones de la AII mas selectivas y especificas han conducido al desarrollo de antagonistas especificos de los receptores de la AII exentos de efectos agonistas y activos por via oral. En las paginas siguientes se revisaran aspectos de la AII como sus tipos de receptores, sus mecanismos de accion, sus acciones fisiologicas y fisiopatologicas, asi como las consecuencias de su antagonismo.

Really does temperature reduction and norepinephrine have similar effects on the energy metabolism in rat brown adipose tissue

Abstract Context: Heat generation by brown adipose tissue (BAT) in response to temperature reduction seems to be entirely related to sympathetic nervous stimulation. Objective: To analyse if temperature reduction and norepinephrine may differently affect the expression of proteins related to energy metabolism in BAT. Materials and methods: Isolated rats BAT was incubated with/without norepinephrine (10–6 mol/L, 24 h at 32 °C and 37 °C). Results: In BAT, 32 °C increased the protein expression levels of carnitine palmitoyltransferase-I and -II, mitochondrial uncoupling protein-1 (UCP-1) and the expression and activity of lactate dehydrogenase. Mitochondrial F1-ATP synthase α-chain expression was decreased at 32 °C compared to 37 °C. Norepinephrine and at 32 °C exposure, UCP-1 expression was increased but cytochrome-c oxidase and F1-ATP synthase α-chain expression was reduced with respect to 37 °C. Discussion: Sympathetic stimulation seems not to be the only factor associated with heat generation. Conclusions: Temperature reduction by itself exerts some different effects on the expression of proteins related to the energy metabolism than norepinephrine.

Papel de la aldosterona en las alteraciones vasculares funcionales y en el proceso inflamatorio asociados a la hipertensión en ratas

Objetives To study the participation of aldosterone in the vascular dysfunction, inflammatory process and vascular oxidative stress associated to hypertension.

Fármacos antihipertensivos y aterogénesis

La reduccion de la presion arterial (PA) mediante el tratamiento antihipertensivo reduce la morbimortalidad cardiovascular en pacientes con hipertension, asi como en pacientes no hipertensos con diversos factores de riesgo cardiovascular. La reduccion de las cifras de PA parece ser el principal mecanismo por el que este tipo de farmacos ejercen sus efectos beneficiosos, ya que a traves de diversos mecanismos disminuyen el desarrollo, la progresion y las complicaciones de la aterosclerosis, base fisiopatologica de la enfermedad vascular y de los accidentes vasculares. Numerosos estudios han puesto de manifiesto que diversas familias de farmacos antihipertensivos, principalmente los inhibidores de la enzima de conversion de la angiotensina y los antagonistas de los repectores de la angiotensina II, algunos antagonistas del cacio, ciertos bloqueadores beta y alfa-antagonistas, tienen efectos antiateroscleroticos y antitromboticos que son independientes de la reduccion de la PA. Los efectos sobre los factores endoteliales, el estres oxidativo, el proceso inflamatorio vascular y el equilibrio fibrinolitico son algunos de los principales mecanismos antiateroscleroticos de los mencionados farmacos antihipertensivos.

Las estatinas como antioxidantes

La produccion local exagerada de especies reactivas de oxigeno, especialmente de aniones superoxido, es un mecanismo importante que subyace al desarrollo aterosclerotico. Como consecuencia de este incremento del estres oxidativo, la posibilidad de oxidacion de las lipoproteinas de baja densidad (LDL) aumenta y estas, a su vez, son capaces de estimular las enzimas implicadas en la produccion de radicales libres, creandose un circulo vicioso. Numerosos estudios realizados con inhibidores de la HMG-CoA reductasa, o estatinas, han demostrado la eficacia de estos farmacos para disminuir la morbimortalidad cardiovascular. Este efecto beneficioso no solo es debido a sus efectos reductores en la sintesis del colesterol, sino tambien a acciones pleiotropicas, entre las que podemos mencionar su efecto antioxidante. Las estatinas inhiben la produccion de aniones superoxido por los macrofagos y celulas endoteliales, ademas de actuar sobre las enzimas y los agentes de la regulacion redox. Asi, las estatinas podrian disminuir la expresion y la actividad de la NAD(P)H oxidasa, reducir las ubicinonas, enzimas implicadas en el transporte mitocondrial de electrones, aumentar la actividad de las enzimas antioxidantes y la oxido nitrico sintasa. Por ello, los efectos antioxidantes de las estatinas podrian contribuir a su eficacia clinica en el tratamiento de enfermedades cardiovasculares, asi como en otras situaciones asociadas a un incremento en el estres oxidativo.