Person: Villalba Orero, María
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First Name
María
Last Name
Villalba Orero
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Veterinaria
Department
Medicina y Cirugía Animal
Area
Medicina y Cirugía Animal
Identifiers
35 results
Search Results
Now showing 1 - 10 of 35
Item The SRSF4–GAS5-Glucocorticoid Receptor Axis Regulates Ventricular Hypertrophy(Circulation Research, 2021) Larrasa-Alonso, Javier; Martí-Gómez, Carlos; López-Olañeta, Marina M.; Rey-Martín, M. Ascensión; Sánchez-Cabo, Fátima; McNicoll, François; Müller-McNicoll, Michaela; García-Pavía, Pablo; Lara-Pezzi, Enrique; Villalba Orero, María; Ortiz Sánchez, PaulaObjective: To investigate the role of SRSF4 in the heart. Methods and Results: Echocardiography of mice specifically lacking SRSF4 in the heart (SRSF4 KO) revealed left ventricular hypertrophy and increased cardiomyocyte area, which led to progressive diastolic dysfunction with age. SRSF4 KO mice showed altered electrophysiological activity under isoproterenol-induced cardiac stress, with a post-QRS depression and a longer QT interval, indicating an elevated risk of sudden cardiac death. RNA-Seq analysis revealed expression changes in several long noncoding RNAs, including GAS5 (growth arrest-specific 5), which we identified as a direct SRSF4 target in cardiomyocytes by individual-nucleotide-resolution cross-linking and immuno-precipitation. GAS5 is a repressor of the GR (glucocorticoid receptor) and was downregulated in SRSF4 KO hearts. This corresponded with elevated GR transcriptional activity in cardiomyocytes, leading to increases in hypertrophy markers and cell size. Furthermore, hypertrophy in SRSF4 KO cardiomyocytes was reduced by overexpressing GAS5. Conclusions: Loss of SRSF4 expression results in cardiac hypertrophy, diastolic dysfunction, and abnormal repolarization. The molecular mechanism underlying this effect involves GAS5 downregulation and consequent elevation of GR transcriptional activity. Our findings may help to develop new therapeutic tools for the treatment of cardiac hypertrophy and myocardial pathology in patients with Cushing syndrome.Item Assessment of myocardial viscoelasticity with Brillouin spectroscopy in myocardial infarction and aortic stenosis models(Scientific Reports, 2021) Villalba Orero, María; Jiménez-Riobóo, Rafael J; Gontán, Nuria; Sanderson, Daniel; López-Olañeta, Marina; García-Pavía, Pablo; Desco, Manuel; Lara-Pezzi, Enrique; Gómez-Gaviro, Maria VictoriaHeart diseases are associated with changes in the biomechanical properties of the myocardial wall. However, there is no modality available to assess myocardial stiffness directly. Brillouin microspectroscopy (mBS) is a consolidated mechanical characterization technique, applied to the study of the viscoelastic and elastic behavior of biological samples and may be a valuable tool for assessing the viscoelastic properties of the cardiac tissue. In this work, viscosity and elasticity were assessed using mBS in heart samples obtained from healthy and unhealthy mice (n = 6 per group). Speckle-tracking echocardiography (STE) was performed to evaluate heart deformation. We found that mBS was able to detect changes in stiffness in the ventricles in healthy myocardium. The right ventricle showed reduced stiffness, in agreement with its increased compliance. mBS measurements correlated strongly with STE data, highlighting the association between displacement and stiffness in myocardial regions. This correlation was lost in pathological conditions studied. The scar region in the infarcted heart presented changes in stiffness when compared to the rest of the heart, and the hypertrophied left ventricle showed increased stiffness following aortic stenosis, compared to the right ventricle. We demonstrate that mBS can be applied to determine myocardial stiffness, that measurements correlate with functional parameters and that they change with disease.Item Correlation between kinematic parameters, ataxia and ground-to-lip distance in detomidine sedated horses(Equine Veterinary Journal, 2024) Izquierdo Moreno, Jorge; Illán de Paz, Marta; Manso Díaz, Gabriel; Villalba Orero, María; López San Román, Francisco JavierBackground An accurate evaluation of the degree of sedation is mandatory to adjust the dosage of sedative drugs. Objectives To determine the correlation between head height above the ground and ataxia degree in horses sedated with detomidine and the correlation existing between accelerometric variables and both parameters. Study design Retrospective study. Methods Twelve horses were given 0.01 mg/kg of detomidine hydrochloride iv. Measured accelerometric parameters, with one accelerometer positioned between both sacral tuberosities, included speed, stride frequency and length, regularity, dorsoventral, longitudinal, mediolateral and total accelerometric activities, relative force index and dorsoventral, longitudinal and mediolateral parts of the accelerometric activities. Head height above the ground (cm) and subjective ataxia degree were also measured. Baseline values (−15 min) and values measured 5 and 15 min after the injection and then every 15 min for a period of 2 h were obtained. Results There was a negative and strong correlation between head height above the ground and ataxia degree (Pearson r = −0.78, p < 0.001), particularly during the first 45 min. A significant correlation was found between head height above the ground and almost all accelerometric parameters. This correlation was very strong with stride frequency, regularity and dorsoventral and total accelerometric activities in both cases, but for ataxia, also with total accelerometric activity. Main limitations Experimental conditions may not represent real clinical situations. Conclusions Stride frequency and regularity are the most reliable parameters to determine degree of sedation and are related to the sedation produced. Ataxia should not be considered a separate property of sedation and does not need to be assessed separately to the depth of sedationItem CD69 expression on regulatory T cells protects from immune damage after myocardial infarction(The Journal of Clinical Investigation, 2022) Rafael Blanco-Domínguez; Hortensia de la Fuente; Cristina Rodríguez; Laura Martín-Aguado; Raquel Sánchez-Díaz; Rosa Jiménez-Alejandre; Iker Rodríguez-Arabaolaza; Andrea Curtabbi; Marcos M. García-Guimaraes; Alberto Vera; Fernando Rivero; Javier Cuesta; Luis J. Jiménez-Borreguero; Alberto Cecconi; Albert Duran-Cambra; Manel Taurón; Judith Alonso; Héctor Bueno; Jose Antonio Enríquez; Simon C. Robson; Fernando Alfonso; Francisco Sánchez-Madrid; José Martínez-González; Pilar Martín; Villalba Orero, MaríaIncreasing evidence has pointed to the important function of T cells in controlling immune homeostasis and pathogenesis after myocardial infarction (MI), although the underlying molecular mechanisms remain elusive. In this study, a broad analysis of immune markers in 283 patients revealed significant CD69 overexpression on Tregs after MI. Our results in mice showed that CD69 expression on Tregs increased survival after left anterior descending (LAD) coronary artery ligation. Cd69-/- mice developed strong IL-17+ γδT cell responses after ischemia that increased myocardial inflammation and, consequently, worsened cardiac function. CD69+ Tregs, by induction of AhR-dependent CD39 ectonucleotidase activity, induced apoptosis and decreased IL-17A production in γδT cells. Adoptive transfer of CD69+ Tregs into Cd69-/- mice after LAD ligation reduced IL-17+ γδT cell recruitment, thus increasing survival. Consistently, clinical data from 2 independent cohorts of patients indicated that increased CD69 expression in peripheral blood cells after acute MI was associated with a lower risk of rehospitalization for heart failure (HF) after 2.5 years of follow-up. This result remained significant after adjustment for age, sex, and traditional cardiac damage biomarkers. Our data highlight CD69 expression on Tregs as a potential prognostic factor and a therapeutic option to prevent HF after MI.Item Functional Impact and Regulation of Alternative Splicing in Mouse Heart Development and Disease(2022) Martí-Gómez,Carlos; Larrasa-Alonso, Javier; López-Olañeta, Marina; García-Pavía, Pablo; Sánchez-Cabo, Fátima; Lara-Pezzi, Enrique; Villalba Orero, MaríaAlternative splicing (AS) plays a major role in the generation of transcript diversity. In the heart, roles have been described for some AS variants, but the global impact and regulation of AS patterns are poorly understood. Here, we studied the AS profiles in heart disease, their relationship with heart development, and the regulatory mechanisms controlling AS dynamics in the mouse heart. We found that AS profiles characterized the different groups and that AS and gene expression changes affected independent genes and biological functions. Moreover, AS changes, specifically in heart disease, were associated with potential protein–protein interaction changes. While developmental transitions were mainly driven by the upregulation of MBNL1, AS changes in disease were driven by a complex regulatory network, where PTBP1 played a central role. Indeed, PTBP1 over-expression was sufficient to induce cardiac hypertrophy and diastolic dysfunction, potentially by perturbing AS patterns.Item Cardiorespiratory, Sedative and Antinociceptive Effects of a Medetomidine Constant Rate Infusion with Morphine, Ketamine or Both(Animals, 2021) Troya-Portillo, Lucas; López-Sanromán, Javier; Villalba Orero, María; Santiago Llorente, IsabelStanding surgery under sedation reduces anesthetic-related mortality in horses. Medetomidine, alone and combined with morphine in a constant rate infusion (CRI), has been described for standing surgery but their cardiorespiratory, sedative and antinociceptive effects have never been compared. The addition of ketamine could improve analgesia in these procedures with minimal cardiorespiratory consequences. The objectives were to compare the cardiorespiratory effects, quality of sedation, antinociception and ataxia produced by administration of a medetomidine-based CRI with morphine, ketamine or both, in standing horses. A prospective, blind, randomized crossover, experimental design with six healthy adult horses was performed, in which four treatments were administered to all horses with at least two weeks of washout period: medetomidine (M); medetomidine and ketamine (MK); medetomidine and morphine (MMo); and medetomidine, morphine and ketamine (MMoK). Dosages were the same in all treatment groups: medetomidine at 5 µg/kg bwt followed by 5 µg/kg bwt/h, ketamine at 0.4 mg/kg/h and morphine at 50 µg/kg bwt, followed by morphine 30 µg/kg bwt/h. Drug infusions were maintained for 120 min. Cardiorespiratory variables, sedation degree and antinociceptive effects were evaluated during the procedure. All combinations produced similar sedation and antinociceptive effects and no clinically relevant alterations in cardiorespiratory variables occurred. Medetomidine CRI combined with morphine, ketamine or both are suitable and safe protocols for standing sedation in horses and the addition of morphine and/or ketamine did not cause any negative effect but no improving effect on sedation and antinociception was detected.Item Cardiovascular imaging: what have we learned from animal models?(Frontiers in Pharmacology, 2015) Santos, Arnoldo; Fernández-Friera, Leticia; López-Melgar, Beatriz; Mateo, Jesús; Jiménez-Borreguero, Jesús; Villalba Orero, María; España Palomares, Samuel; Mota Blanco, Rubén Avelino; Ruiz-Cabello Osuna, JesúsItem Loss of SRSF3 in Cardiomyocytes Leads to Decapping of Contraction-Related mRNAs and Severe Systolic Dysfunction(Circulation Research, 2019) Ortiz-Sánchez, Paula; Villalba Orero, María; López-Olañeta, Marina M.; Larrasa-Alonso, Javier; Sánchez-Cabo, Fátima; Martí-Gómez, Carlos; Camafeita, Emilio; Gómez-Salinero, Jesús M.; Ramos-Hernández, Laura; Nielsen, Peter J.; Vázquez, Jesús; Müller-McNicoll, Michaela; García-Pavía, Pablo; Lara-Pezzi, EnriqueRationale: RBPs (RNA binding proteins) play critical roles in the cell by regulating mRNA transport, splicing, editing, and stability. The RBP SRSF3 (serine/arginine-rich splicing factor 3) is essential for blastocyst formation and for proper liver development and function. However, its role in the heart has not been explored. Objective: To investigate the role of SRSF3 in cardiac function. Methods and Results: Cardiac SRSF3 expression was high at mid gestation and decreased during late embryonic development. Mice lacking SRSF3 in the embryonic heart showed impaired cardiomyocyte proliferation and died in utero. In the adult heart, SRSF3 expression was reduced after myocardial infarction, suggesting a possible role in cardiac homeostasis. To determine the role of this RBP in the adult heart, we used an inducible, cardiomyocyte-specific SRSF3 knockout mouse model. After SRSF3 depletion in cardiomyocytes, mice developed severe systolic dysfunction that resulted in death within 8 days. RNA-Seq analysis revealed downregulation of mRNAs encoding sarcomeric and calcium handling proteins. Cardiomyocyte-specific SRSF3 knockout mice also showed evidence of alternative splicing of mTOR (mammalian target of rapamycin) mRNA, generating a shorter protein isoform lacking catalytic activity. This was associated with decreased phosphorylation of 4E-BP1 (eIF4E-binding protein 1), a protein that binds to eIF4E (eukaryotic translation initiation factor 4E) and prevents mRNA decapping. Consequently, we found increased decapping of mRNAs encoding proteins involved in cardiac contraction. Decapping was partially reversed by mTOR activation. Conclusions: We show that cardiomyocyte-specific loss of SRSF3 expression results in decapping of critical mRNAs involved in cardiac contraction. The molecular mechanism underlying this effect likely involves the generation of a short mTOR isoform by alternative splicing, resulting in reduced 4E-BP1 phosphorylation. The identification of mRNA decapping as a mechanism of systolic heart failure may open the way to the development of urgently needed therapeutic tools. (Circ Res. 2019;125:170-183. DOI: 10.1161/CIRCRESAHA.118.314515.)Item Reducción de las necesidades de isoflurano mediante el empleo de combinaciones analgésicas e hipnóticas en el caballo(2015) Villalba Orero, María; Álvarez Gómez de Segura, IgnacioItem A Prototype of a Decision Support System for Equine Cardiovascular Diseases Diagnosis and Management(Mathematics, 2021) Villalba Orero, María; Roanes Lozano, EugenioProper diagnosis and management of equine cardiac diseases require a broad experience and a specialization in the field, but acquisition of specific knowledge is difficult, due, among other reasons, to the limited literature in this field. Therefore, we have designed, developed, and implemented (on a computer algebra system) a Decision Support System (DSS) for equine cardiovascular diseases diagnosis and management based on clinical practise. At this step it is appropriate for equine science teaching, but this work paves the way for a clinical decision support system that facilitated equine clinicians the management of horses with cardiac diseases, allowing improving health care in this species. The latter would require extensive testing prior to its use. The novelty of this work relies on the organization of the equine cardiology workflow in mathematical logic form, that allowed designing, develop and implement a DSS in this new field. An innovation of this work is the part of the DSS devoted to data completion (motivated by the possible lack of specialization of the users—the veterinarians).