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
7 results
Search Results
Now showing 1 - 7 of 7
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 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 Activation of Serine One-Carbon Metabolism by Calcineurin Aβ1 Reduces Myocardial Hypertrophy and Improves Ventricular Function(Journal of the American College of Cardiology, 2018) Laura Padrón-Barthe, Laura; Villalba Orero, María; Gómez-Salinero, Jesús M.; Rebeca Acín-Pérez, Rebeca; Sara Cogliati, Sara; López-Olañeta, Marina; Ortiz Sánchez, Paula; Bonzón-Kulichenko, Elena; Vázquez. Jesús; García-Pavía, Pablo; Rosenthal, Nadia; Enríquez, José Antonio; Lara-Pezzi, EnriqueBackground: In response to pressure overload, the heart develops ventricular hypertrophy that progressively decompensates and leads to heart failure. This pathological hypertrophy is mediated, among others, by the phosphatase calcineurin and is characterized by metabolic changes that impair energy production by mitochondria. Objectives: The authors aimed to determine the role of the calcineurin splicing variant CnAβ1 in the context of cardiac hypertrophy and its mechanism of action. Methods: Transgenic mice overexpressing CnAβ1 specifically in cardiomyocytes and mice lacking the unique C-terminal domain in CnAβ1 (CnAβ1Δi12 mice) were used. Pressure overload hypertrophy was induced by transaortic constriction. Cardiac function was measured by echocardiography. Mice were characterized using various molecular analyses. Results: In contrast to other calcineurin isoforms, the authors show here that cardiac-specific overexpression of CnAβ1 in transgenic mice reduces cardiac hypertrophy and improves cardiac function. This effect is mediated by activation of serine and one-carbon metabolism, and the production of antioxidant mediators that prevent mitochondrial protein oxidation and preserve ATP production. The induction of enzymes involved in this metabolic pathway by CnAβ1 is dependent on mTOR activity. Inhibition of serine and one-carbon metabolism blocks the beneficial effects of CnAβ1. CnAβ1Δi12 mice show increased cardiac hypertrophy and declined contractility. Conclusions: The metabolic reprogramming induced by CnAβ1 redefines the role of calcineurin in the heart and shows for the first time that activation of the serine and one-carbon pathway has beneficial effects on cardiac hypertrophy and function, paving the way for new therapeutic approachItem Systolic Dysfunction in Infarcted Mice Does Not Necessarily Lead to Heart Failure: Need to Refine Preclinical Models(Journal of cardiovascular translational research, 2017) Villalba Orero, María; López-Olañeta, Marina; García-Pavía, Pablo; Lara-Pezzi, EnriqueHeart failure (HF) is a major cause of death and hospitalization worldwide. Despite advances in reducing mortality, prognosis remains poor and prevalence has reached epidemic proportions. The limitations of available preclinical models represent a major hurdle in the development of new therapies. Myocardial infarction (MI) is a main cause of HF in humans, and mouse models of MI are often used to study HF mechanisms and experimental treatments. We investigated whether MI in mice constitutes an appropriate model of HF. Permanent ligation of the left coronary artery induced severe and persistent systolic dysfunction and ventricular dilatation. Mouse follow-up for 10 months showed no significant evidence of lung congestion or other pulmonary defects associated with HF. No difference was observed in the capacity of infarcted mice to exercise compared to control animals. These results indicate that severe cardiac dysfunction in mice is not sufficient to demonstrate the presence of HFItem Severe Cardiac Dysfunction and Death Caused by Arrhythmogenic Right Ventricular Cardiomyopathy Type 5 Are Improved by Inhibition of Glycogen Synthase Kinase-3β(Circulation, 2019) Padrón-Barthe, Laura; Gómez-Salinero, Jesús M.; Domínguez, Fernando; Román, Marta; Larrasa-Alonso, Javier; Martínez, Fernando; López-Olañeta, Marina; Bonzón-Kulichenko, Elena; Vázquez, Jesús; Martí-Gómez, Carlos; Santiago, Demetrio J.; Prados, Belén; Giovinazzo, Giovanna; Gómez-Gaviro, María Victoria; Priori, Silvia; Garcia-Pavia, Pablo; Lara-Pezzi, Enrique; Villalba Orero, María; Ortiz Sánchez, PaulaBACKGROUND: Arrhythmogenic cardiomyopathy/arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease characterized by fibrofatty replacement of the myocardium, resulting in heart failure and sudden cardiac death. The most aggressive arrhythmogenic cardiomyopathy/ARVC subtype is ARVC type 5 (ARVC5), caused by a p.S358L mutation in TMEM43 (transmembrane protein 43). The function and localization of TMEM43 are unknown, as is the mechanism by which the p.S358L mutation causes the disease. Here, we report the characterization of the first transgenic mouse model of ARVC5. METHODS: We generated transgenic mice overexpressing TMEM43 in either its wild-type or p.S358L mutant (TMEM43-S358L) form in postnatal cardiomyocytes under the control of the α-myosin heavy chain promoter. RESULTS: We found that mice expressing TMEM43-S358L recapitulate the human disease and die at a young age. Mutant TMEM43 causes cardiomyocyte death and severe fibrofatty replacement. We also demonstrate that TMEM43 localizes at the nuclear membrane and interacts with emerin and β-actin. TMEM43-S358L shows partial delocalization to the cytoplasm, reduced interaction with emerin and β-actin, and activation of glycogen synthase kinase-3β (GSK3β). Furthermore, we show that targeting cardiac fibrosis has no beneficial effect, whereas overexpression of the calcineurin splice variant calcineurin Aβ1 results in GSK3β inhibition and improved cardiac function and survival. Similarly, treatment of TMEM43 mutant mice with a GSK3β inhibitor improves cardiac function. Finally, human induced pluripotent stem cells bearing the p.S358L mutation also showed contractile dysfunction that was partially restored after GSK3β inhibition. CONCLUSIONS: Our data provide evidence that TMEM43-S358L leads to sustained cardiomyocyte death and fibrofatty replacement. Overexpression of calcineurin Aβ1 in TMEM43 mutant mice or chemical GSK3β inhibition improves cardiac function and increases mice life span. Our results pave the way toward new therapeutic approaches for ARVC5.Item Early Preventive Treatment With Enalapril Improves Cardiac Function and Delays Mortality in Mice With Arrhythmogenic Right Ventricular Cardiomyopathy Type 5(Circulation: Heart Failure, 2021) Domínguez, Fernando; Lalaguna, Laura; López-Olañeta, Marina; Padrón-Barthe, Laura; Román, Marta; Bello-Arroyo, Elísabet; Briceño, Ana; Gonzalez-Lopez, Esther; Segovia-Cubero, Javier; García-Pavía, Pablo; Lara-Pezzi, Enrique; Villalba Orero, MaríaBackground: Arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5) is an inherited cardiac disease with complete penetrance and an aggressive clinical course caused by mutations in TMEM43 (transmembrane protein 43). There is no cure for ARVC5 and palliative treatment is started once the phenotype is present. A transgenic mouse model of ARVC5 expressing human TMEM43-S358L (TMEM43mut) recapitulates the human disease, enabling the exploration of preventive treatments. The aim of this study is to determine whether preventive treatment with heart failure drugs (β-blockers, ACE [angiotensin-converting enzyme] inhibitors, mineralocorticoid-receptor antagonists) improves the disease course of ARVC5 in TMEM43mut mice. Methods: TMEM43mut male/female mice were treated with metoprolol (β-blockers), enalapril (ACE inhibitor), spironolactone (mineralocorticoid-receptor antagonist), ACE inhibitor + mineralocorticoid-receptor antagonist, ACE inhibitor + mineralocorticoid-receptor antagonist + β-blockers or left untreated. Drugs were initiated at 3 weeks of age, before ARVC5 phenotype, and serial ECG and echocardiograms were performed. Results: TMEM43mut mice treated with enalapril showed a significantly increased median survival compared with untreated mice (26 versus 21 weeks; P=0.003). Enalapril-treated mice also exhibited increased left ventricular ejection fraction at 4 months compared with controls (37.0% versus 24.9%; P=0.004), shorter QRS duration and reduced left ventricle fibrosis. Combined regimens including enalapril also showed positive effects. Metoprolol decreased QRS voltage prematurely and resulted in a nonsignificant decrease in left ventricular ejection fraction compared with untreated TMEM43mut mice. Conclusions: Preventive enalapril-based regimens reduced fibrosis, improved ECG, echocardiographic parameters and survival of ARVC5 mice. Early metoprolol did not show positive effects and caused premature ECG abnormalities. Our findings pave the way to consider prophylactic enalapril in asymptomatic ARVC5 genetic carriers.Item Lafora Disease Is an Inherited Metabolic Cardiomyopathy(Journal of the American College of Cardiology, 2017) Villalba Orero, María; Gentzane Sánchez-Elexpuru, Gentzane; López-Olañeta, Marina; Campuzano, Oscar; Bello-Arroyo, Elisabet; García-Pavía, Pablo; Serratosa, José M.; Brugada, Ramón; Sánchez, Marina P.; Lara-Pezzi, Enrique