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Instituto de Salud Carlos III (ISCIII)/ FEDER, Depto. de Fisiología, Depto. de Medicina, Fac. de Medicina, TRUE, pub

Aerobic exercise training (ET) produces beneficial adaptations in skeletal muscles, including angiogenesis. The renin–angiotensin system (RAS) is highly involved in angiogenesis stimuli. However, the molecular mechanisms underlying capillary growth in skeletal muscle induced by aerobic ET are not completely understood. This study aimed to investigate the effects of volume-dependent aerobic ET on skeletal muscle angiogenesis involving the expression of miRNAs-27a and 27b on RAS and oxidant–antioxidant balance. Eight-week-old female Wistar rats were divided into three groups: sedentary control (SC), trained protocol 1 (P1), and trained protocol 2 (P2). P1 consisted of 60 min/day of swimming, 5×/week, for 10 weeks. P2 consisted of the same protocol as P1 until the 8th week, but in the 9th week, rats trained 2×/day, and in the 10th week, trained 3×/day. Angiogenesis and molecular analyses were performed in soleus muscle samples. Furthermore, to establish ET-induced angiogenesis through RAS, animals were treated with an AT1 receptor blocker (losartan). Aerobic ET promoted higher VO2 peak and exercise tolerance values. In contrast, miRNA-27a and -27b levels were reduced in both trained groups, compared with the SC group. This was in parallel with an increase in the ACE1/Ang II/VEGF axis, which led to a higher capillary-to-fiber ratio. Moreover, aerobic ET induced an antioxidant profile increasing skeletal muscle SOD2 and catalase gene expression, which was accompanied by high nitrite levels and reduced nitrotyrosine concentrations in the circulation. Additionally, losartan treatment partially re-established the miRNAs expression and the capillary-to-fiber ratio in the trained groups. In summary, aerobic ET promoted angiogenesis through the miRNA-27a/b–ACE1/Ang II/VEGF axis and improved the redox balance. Losartan treatment demonstrates the participation of RAS in ET-induced vascular growth. miRNAs and RAS components are promising potential targets to modulate angiogenesis, Depto. de Fisiología, Fac. de Medicina, TRUE, pub

We have evaluated cardiac function and fibrosis in infarcted male Wistar rats treated with MitoQ (50 mg/kg/day) or vehicle for 4 weeks. A cohort of patients admitted with a first episode of acute MI were also analyzed with cardiac magnetic resonance and T1 mapping during admission and at a 12-month follow-up. Infarcted animals presented cardiac hypertrophy and a reduction in the left ventricular ejection fraction (LVEF) and E- and A-waves (E/A) ratio when compared to controls. Myocardial infarction (MI) rats also showed cardiac fibrosis and endoplasmic reticulum (ER) stress activation. Binding immunoglobulin protein (BiP) levels, a marker of ER stress, were correlated with collagen I levels. MitoQ reduced oxidative stress and prevented all these changes without affecting the infarct size. The LVEF and E/A ratio in patients with MI were 57.6 ± 7.9% and 0.96 ± 0.34, respectively. No major changes in cardiac function, extracellular volume fraction (ECV), or LV mass were observed at follow-up. Interestingly, the myeloperoxidase (MPO) levels were associated with the ECV in basal conditions. BiP staining and collagen content were also higher in cardiac samples from autopsies of patients who had suffered an MI than in those who had died from other causes. These results show the interactions between mitochondrial oxidative stress and ER stress, which can result in the development of diffuse fibrosis in the context of MI., Unión Europea, Instituto de Salud Carlos III, Depto. de Fisiología, Fac. de Medicina, TRUE, pub

El presente proyecto de innovación docente se basa en la utilización de la red social Instagram para incentivar el estudio diario y el aprendizaje cooperativo de una forma lúdica, autónoma y divertida. Se aplicó en la docencia de la Fisiología Humana en distintos grados en los que participa el Departamento de Fisiología. La metodología consiste en que los alumnos, trabajando en grupo, publiquen contenidos en Instagram, para repasar, sintetizar y compartir información de la asignatura. Los objetivos alcanzados fueron: motivación en el estudio continuado, implicación en el proceso de aprendizaje, trabajo en equipo y adquisición de competencias transversales como creatividad, liderazgo y compromiso. La participación en el proyecto fue muy alta (94%), así como la satisfacción de los alumnos, sobre todo en aspectos motivacionales (interés y curiosidad por la asignatura) y de integración, gracias al trabajo en equipo. En conclusión, la red Instagram es una herramienta útil como complemento de las clases, con objeto de incentivar el estudio diario, sintetizar la información y transmitirla mediante trabajo cooperativo.

Cardiorenal syndrome is a term that defines the complex bidirectional nature of the interaction between cardiac and renal disease. It is well established that patients with kidney disease have higher incidence of cardiovascular comorbidities and that renal dysfunction is a significant threat to the prognosis of patients with cardiac disease. Fibrosis is a common characteristic of organ injury progression that has been proposed not only as a marker but also as an important driver of the pathophysiology of cardiorenal syndromes. Due to the relevance of fibrosis, its study might give insight into the mechanisms and targets that could potentially be modulated to prevent fibrosis development. The aim of this review was to summarize some of the pathophysiological pathways involved in the fibrotic damage seen in cardiorenal syndromes, such as inflammation, oxidative stress and endoplasmic reticulum stress, which are known to be triggers and mediators of fibrosis., Instituto de Salud Carlos III (ISCIII)/ FEDER, Depto. de Fisiología, Depto. de Medicina, Fac. de Medicina, TRUE, pub

El objetivo del proyecto de innovación docente que se presenta fue mejorar la capacidad de análisis crítico del conocimiento científico en el alumnado del Grado de Medicina a través del uso de Twitter. Los estudiantes de la asignatura de Fisiología Humana compartieron a través de Twitter noticias científicas relacionadas con la asignatura. Tras una selección previa, el profesorado publicó un periódico online y los alumnos presentaron una de las noticias publicadas. Se realizó una encuesta online de evaluación del proyecto utilizando escalas de Likert (1-10). Los estudiantes respondieron que el proyecto había aumentado su capacidad de análisis crítico de la investigación biomédica (7,65; ds=1,71) y que la metodología había aumentado su interés por la asignatura (8,05; ds=1,69). La utilización de Twitter combinada con la exposición de noticias científicas resultó útil para mejorar la capacidad de análisis crítico de la evidencia científica biomédica, competencia básica del Grado de Medicina.

Secreted phospholipase A2-IIA (sPLA2-IIA) is a pro-inflammatory protein associated with cardiovascular disorders, whose functions and underlying mechanisms in cardiac remodelling are still under investigation. We herein study the role of sPLA2-IIA in cardiac fibroblast (CFs)-to-myofibroblast differentiation and fibrosis, two major features involved in cardiac remodelling, and also explore potential mechanisms involved. In a mice model of dilated cardiomyopathy (DCM) after autoimmune myocarditis, serum and cardiac sPLA2-IIA protein expression were found to be increased, together with elevated cardiac levels of the cross-linking enzyme lysyl oxidase (LOX) and reactive oxygen species (ROS) accumulation. Exogenous sPLA2-IIA treatment induced proliferation and differentiation of adult rat CFs. Molecular studies demonstrated that sPLA2-IIA promoted Src phosphorylation, shedding of the membrane-anchored heparin-binding EGF-like growth factor (HB-EGF) ectodomain and EGFR phosphorylation, which triggered phosphorylation of ERK, P70S6K and rS6. This was also accompanied by an up-regulated expression of the bone morphogenic protein (BMP)-1, LOX and collagen I. ROS accumulation were also found to be increased in sPLA2-IIA-treated CFs. The presence of inhibitors of the Src/ADAMs-dependent HB-EGF shedding/EGFR pathway abolished the CF phenotype induced by sPLA2-IIA. In conclusion, sPLA2-IIA may promote myofibroblast differentiation through its ability to modulate EGFR transactivation and signalling as key mechanisms that underlie its biological and pro-fibrotic effects., Ministerio de Economía y Competitividad (MINECO)/FEDER, Instituto de Salud Carlos III (ISCIII), Depto. de Fisiología, Fac. de Medicina, TRUE, pub

Lysyl oxidases (LOX and LOX-likes (LOXLs) isoenzymes) belong to a family of copper-dependent enzymes classically involved in the covalent cross-linking of collagen and elastin, a pivotal process that ensures extracellular matrix (ECM) stability and provides the tensile and elastic characteristics of connective tissues. Besides this structural role, in the last years, novel biological properties have been attributed to these enzymes, which can critically influence cardiovascular function. LOX and LOXLs control cell proliferation, migration, adhesion, differentiation, oxidative stress, and transcriptional regulation and, thereby, their dysregulation has been linked to a myriad of cardiovascular pathologies. Lysyl oxidase could modulate virtually all stages of the atherosclerotic process, from endothelial dysfunction and plaque progression to calcification and rupture of advanced and complicated plaques, and contributes to vascular stiffness in hypertension. The alteration of LOX/LOXLs expression underlies the development of other vascular pathologies characterized by a destructive remodeling of the ECM, such as aneurysm and artery dissections, and contributes to the adverse myocardial remodeling and dysfunction in hypertension, myocardial infarction, and obesity. This review examines the most recent advances in the study of LOX and LOXLs biology and their pathophysiological role in cardiovascular diseases with special emphasis on their potential as therapeutic targets., Ministerio de Economía y Competitividad (MINECO), Instituto de Salud Carlos III (ISCIII), Agencia de Gestio d’Ajuts Universitaris i de Recerca (AGAUR), Depto. de Fisiología, Fac. de Medicina, TRUE, pub

La obesidad se define como una excesiva acumulación de grasa debido a undesequilibrio entre las calorías consumidas y gastadas. La obesidad mundial ha crecido dramáticamente en las últimas décadas por lo que no es sorprendente que numerosos estudios se hayan llevado a cabo para investigar su efecto dañino sobre la salud humana.Una de las características de los pacientes obesos es la presencia de adipocitos más grandes los cuáles una vez alcanzado su límite de expansión tienen una menor capacidad de almacenamiento de grasa dando lugar a un aumento de los niveles de ácidos grasos circulantes los cuales se pueden depositar en tejidos no adiposos, incluido el corazón, ejerciendo efectos tóxicos en los mismos. Además, la obesidad se asocia con alteraciones estructurales y funcionales en el corazón las cuales pueden dar lugar a disfunción cardiaca. De hecho, las enfermedades cardiovasculares son la primera causa de muerte en individuos con obesidad o diabetes. Entre los mecanismos que contribuyen a la aparición de alteraciones estructurales y funcionales se encuentran la lipotoxicidad cardiaca, las alteraciones en el uso de sustratos metabólicos, mediadores profibróticos como Galectina 3 (Gal-3), la disfunción mitocondrial y el estrés oxidativo, los cuales facilitan el desarrollo de fibrosis cardiaca con consecuencias funcionales. Niveles patológicos de especies reactivas de oxígeno siendo la mitocondria la principal fuente de los mismos, se ha demostrado que tienen un efecto dañino en el corazón..., Obesity is defined as an abnormal or excessive fat accumulation due to an energy imbalance between calories consumed and expended. Worldwide obesity has grown dramatically in the last decades so it is not surprising that numerous studies have been performed to investigate its harmful effect on human health. One of the characteristics of obese patients is the presence of larger adipocytes which reach a limit and have diminished capacity to store fat, thereby leading to elevation of circulating fatty acids which can deposit in non-adipose tissues, including the heart,exerting toxic effects. Moreover, obesity is associated with structural and functional alterations in the heart that can lead to cardiac dysfunction. In fact, cardiovascular disease is the primary cause of death in individuals with obesity and diabetes. Among the mechanisms that contribute to cardiac structural and functional alterations, cardiac lipotoxicity, alterations in the use of metabolic substrates, profibrotic mediators such as Galectin-3 (Gal-3), mitochondrial dysfunction and oxidative stress are some of these which facilitate the development of cardiac fibrosis with functional consequences. Pathological ROS levels have been demonstrated to have harmful effects in the heart, with the mitochondria being the main source of ROS. Moreover, oxidative stress can also participate in the adipose tissue remodelling which can be underlying metabolic alterations associated with obesity...

La obesidad se define como una excesiva acumulación de grasa debido a undesequilibrio entre las calorías consumidas y gastadas. La obesidad mundial ha crecido dramáticamente en las últimas décadas por lo que no es sorprendente que numerosos estudios se hayan llevado a cabo para investigar su efecto dañino sobre la salud humana.Una de las características de los pacientes obesos es la presencia de adipocitos más grandes los cuáles una vez alcanzado su límite de expansión tienen una menor capacidad de almacenamiento de grasa dando lugar a un aumento de los niveles de ácidos grasos circulantes los cuales se pueden depositar en tejidos no adiposos, incluido el corazón, ejerciendo efectos tóxicos en los mismos. Además, la obesidad se asocia con alteraciones estructurales y funcionales en el corazón las cuales pueden dar lugar a disfunción cardiaca. De hecho, las enfermedades cardiovasculares son la primera causa de muerte en individuos con obesidad o diabetes. Entre los mecanismos que contribuyen a la aparición de alteraciones estructurales y funcionales se encuentran la lipotoxicidad cardiaca, las alteraciones en el uso de sustratos metabólicos, mediadores profibróticos como Galectina 3 (Gal-3), la disfunción mitocondrial y el estrés oxidativo, los cuales facilitan el desarrollo de fibrosis cardiaca con consecuencias funcionales. Niveles patológicos de especies reactivas de oxígeno siendo la mitocondria la principal fuente de los mismos, se ha demostrado que tienen un efecto dañino en el corazón...

Galectin-3 (Gal-3) is involved in cardiovascular fibrosis and aortic valve (AV) calcification. We hypothesized that Gal-3 pharmacological inhibition with modified citrus pectin (MCP) could reduce aortic and AV remodeling in normotensive rats with pressure overload (PO). Six weeks after aortic constriction, vascular Gal-3 expression was up-regulated in male Wistar rats. Gal-3 overexpression was accompanied by an increase in the aortic media layer thickness, enhanced total collagen, and augmented expression of fibrotic mediators. Further, vascular inflammatory markers as well as inflammatory cells content were greater in aorta from PO rats. MCP treatment (100 mg/kg/day) prevented the increase in Gal-3, media thickness, fibrosis, and inflammation in the aorta of PO rats. Gal-3 levels were higher in AVs from PO rats. This paralleled enhanced AV fibrosis, inflammation, as well as greater expression of calcification markers. MCP treatment prevented the increase in Gal-3 as well as fibrosis, inflammation, and calcification in AVs. Overall, Gal-3 is overexpressed in aorta and AVs from PO rats. Gal-3 pharmacological inhibition blocks aortic and AV remodeling in experimental PO. Gal-3 could be a new therapeutic approach to delay the progression and the development of aortic remodeling and AV calcification in PO., Unión Europea. FP7, Instituto de Salud Carlos III (ISCIII)/FEDER, Fondo de Investigaciones Sanitarias, Red de Investigación Cardiovascular, French National Research Agency (ANR), Depto. de Fisiología, Fac. de Medicina, TRUE, pub

Fasting and postprandial triglyceride concentrations largely depend on dietary and lifestyle factors. Alcohol intake is associated with triglycerides, but the effect of alcohol on diurnal triglyceridemia in a free living situation is unknown. During three days, 139 men (range: 18–80 years) measured their own capillary triglyceride (cTG) concentrations daily on six fixed time-points before and after meals, and the total daily alcohol intake was recorded. The impact of daily alcohol intake (none; low, <10 g/day; moderate, 10–30 g/day; high, >30 g/day) on diurnal triglyceridemia was analyzed by the incremental area under the cTG curve (∆cTG-AUC) reflecting the mean of the six different time-points. Fasting cTG were similar between the alcohol groups, but a trend of increased cTG was observed in men with moderate and high alcohol intake after dinner and at bedtime (p for trend <0.001) which persisted after adjustment for age, smoking and body mass index. The ∆cTG-AUC was significantly lower in males with low alcohol intake (3.0 ± 1.9 mmol·h/L) (n = 27) compared to males with no (7.0 ± 1.8 mmol·h/L) (n = 34), moderate (6.5 ± 1.8 mmol·h/L) (n = 54) or high alcohol intake (7.2 ± 2.2 mmol·h/L) (n = 24), when adjusted for age, smoking and body mass index (adjusted p value < 0.05). In males, low alcohol intake was associated with decreased diurnal triglyceridemia, whereas moderate and high alcohol intake was associated with increased triglycerides after dinner and at bed time., Instituto de Salud Carlos III (ISCIII), Depto. de Fisiología, Depto. de Medicina, Fac. de Medicina, TRUE, pub

[ABSTRACT]Different alcohol beverages have not the same effect on triglyceridemia, inflammation and oxidative stress but this results are controversial and scanty in some aspects. Our objective was to examine the effect of alcohol intake in diurnal triglyceridemia in general population in a free-living situation and its association to usCRP concentrations. Also, we analyse the effect of different alcohol beverages after a fat enriched diet on lipid profile, inflammatory factors and oxidative stress in healthy people in a controlled situation. During 3 days, 273 volunteers measured their own cTG concentrations on six fixed time-points daily and recorded their alcohol intake. The impact of daily alcohol intake (none, low <10g/day; moderate 10-30 g/day; high >30g/day) on cTG was analyzed and stratified for gender. usCRP measurements were collected from 80 subjects from this cohort. Secondly, we have performed a cross-over design in five different weeks. 16 healthy young volunteers received the same oral fat-enriched diet (1486 kcal/m2) and 16 g/m2 of alcohol. In each week the alcoholic beverage was different (red wine, vodka, brandy ,rum). In the control phase, the caloric intake of alcohol was replaced with sugar and water. We measured the levels of serum lipids, usCRP, TNF-α, sPLA2, LPO and TAC. Fasting cTG were similar between the alcohol groups in males. In females fasting cTG were lowest in those with low and moderate alcohol intake and higher in women with high alcohol intake (p <0.05). The mean diurnal triglyceridemia (ΔcTG-AUC), was lower in males with low alcohol intake compared to males with no, moderate or high alcohol intake, when adjusted for age, smoking and BMI (p <0.05). No significant differences were found in females. High alcohol intake was associated to higher usCRP concentrations in females but not in males. usCRP concentrations were associated to alcohol intake and fasting TG in females after adjustment for age, smoking and BMI. Red wine intake wa

The effect of adiponectin and leptin on the proliferation of the human microvascular endothelial cell line (HMEC-1) was studied in the absence or presence of fetal bovine serum (FBS). The participation of extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase/Akt (PI-3K/Akt) pathways in this effect were evaluated. We studied the effect of both adipokines on the motility, mitosis, proliferation and cell death processes of HMEC-1 cells using live-cell imaging techniques. Adiponectin but not leptin further increased the proliferative effect induced by FBS on HMEC-1. This effect seems to be the consequence of an increase in the mitotic index in adiponectin-treated cells when compared to untreated ones. The presence of either the mitogen-activated protein kinase (MAPK) inhibitor (PD98059), or PI-3K inhibitor (LY294002), reduced the effect of adiponectin in a dose-dependent manner. Neither adipokine was able to affect HMEC-1 proliferation in FBS-free conditions. Duration of mitosis, cell motility and the cell death process were similar in all conditions. These data suggest that adiponectin and leptin exert different effects on endothelial cell function. Adiponectin was able to potentiate proliferation of HMEC-1. This effect involves the activation of both PI3-K/Akt and ERK/MAPK pathways. However, it seems to exert minimal effects on HMEC-1 function in the case of leptin, Fondo de Investigaciones Sanitarias, Mutua Madrileña, Red Cardiovascular del FIS, Depto. de Estadística e Investigación Operativa, Depto. de Inmunología, Oftalmología y ORL, Fac. de Ciencias Matemáticas, Fac. de Medicina, TRUE, pub

1. La hipertensión en ratas (SHR) está asociada a las siguientes alteraciones: • Un aumento del área de la aorta, de la media y de la luz vascular, así como del cociente media/lumen en la aorta de SHR. Estas alteraciones estructurales van acompañadas de un aumento de la expresión vascular y producción proteica del factor profibrótico CTGF y producción de colágeno. • Una disfunción vascular caracterizada por la disminución de la relajación endotelio dependiente a Ach, una disminución de la relajación a isoproterenol, un aumento de la contracción a AI y a AII, un aumento de la vasoconstricción dependiente de endotelio a Ach+LNAME y una disminución de la contracción a KCl y FE. No se modifica la respuesta a NPS, ni la expresión vascular del ARNm de eNOS, sin embargo la expresión de p22phox aumenta indicando un aumento de estrés oxidativo vascular. • Una disminución del GSH, y un aumento del GSSG, así como una reducción del cociente GSH/GSSG. Disminución de la actividad de enzima antioxidante GPx y aumento de la actividad de GRed, indicando una reducción de la defensa antioxidante. Además se asocia a un aumento de los niveles hepáticos de MDA sugiriendo un aumento del estrés oxidativo hepático, así como del estado redox sistémico. • Un aumento de las citoquinas inflamatorias plasmáticas IL-1β e IL-6, así como un aumento de la expresión del ARNm de las citoquinas IL-1β, IL-6 y TNF-α en aorta, indicando la presencia de un proceso inflamatorio sistémico y vascular. No se modifica la PCR o el INF-γ. • Un aumento en la expresión génica del p105 (precursor de la subunidad p50 del NFκB) así como una reducción de su inhibidor IκB, lo que sugiere que el sistema NFκB / IκB estaría implicado en la regulación de las citoquinas inflamatorias. 2. El tratamiento con candesartán (2mg/Kg/día) durante 10 semanas en las ratas espontáneamente hipertensas produce: • Una reducción los niveles de presión arterial pero no se normalizan. • Una disminución del área de la media, de la luz vascula

Esta tesis estudia los efectos del envejecimiento sobre la función vascular en la aorta aislada de ratas espontáneamente hipertensas (SHR), y las consecuencias del bloqueo del sistema renina-angiotensina mediante: 1) el tratamiento antihipertensivo crónico de los animales con un inhibidor de la enzima de conversión de angiotensina, Captopril, o con un antagonista de los receptores AT1 de angiotensina II (AII), Losartán, 2) la preincubación de los anillos aórticos con uno u otro fármaco. El envejecimiento incrementa la respuesta a vasoconstrictores con acción sistémica como la AII y un agonista adrenérgico, fenilefrina, mientras que reduce la respuesta a los vasoconstrictores derivados del endotelio, y disminuye la relajación dependiente e independiente de endotelio en la SHR. Losartán y Captopril administrados crónicamente redujeron la presión arterial en la SHR. Tanto el tratamiento antihipertensivo como la preincubación de los anillos con losartán reduce el incremento de la respuesta a AII y a fenilefrína producido por el envejecimiento. El tratamiento, así como la preincubación de los anillos con Losartán y Captopril también mejoró la empeorada relajación dependiente e independiente de endotelio. De estos datos se deduce que la AII, a través de los receptores AT1, es responsable en gran parte de las alteraciones vasculares producidas por el envejecimiento en la SHR y que la mejora inducida por el tratamiento depende principalmente de la inhibición de la AII, más que de su efecto antihipertensivo

Esta tesis estudia los efectos del envejecimiento sobre la función vascular en la aorta aislada de ratas espontáneamente hipertensas (SHR), y las consecuencias del bloqueo del sistema renina-angiotensina mediante: 1) el tratamiento antihipertensivo crónico de los animales con un inhibidor de la enzima de conversión de angiotensina, Captopril, o con un antagonista de los receptores AT1 de angiotensina II (AII), Losartán, 2) la preincubación de los anillos aórticos con uno u otro fármaco. El envejecimiento incrementa la respuesta a vasoconstrictores con acción sistémica como la AII y un agonista adrenérgico, fenilefrina, mientras que reduce la respuesta a los vasoconstrictores derivados del endotelio, y disminuye la relajación dependiente e independiente de endotelio en la SHR. Losartán y Captopril administrados crónicamente redujeron la presión arterial en la SHR. Tanto el tratamiento antihipertensivo como la preincubación de los anillos con losartán reduce el incremento de la respuesta a AII y a fenilefrína producido por el envejecimiento. El tratamiento, así como la preincubación de los anillos con Losartán y Captopril también mejoró la empeorada relajación dependiente e independiente de endotelio. De estos datos se deduce que la AII, a través de los receptores AT1, es responsable en gran parte de las alteraciones vasculares producidas por el envejecimiento en la SHR y que la mejora inducida por el tratamiento depende principalmente de la inhibición de la AII, más que de su efecto antihipertensivo