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
5 results
Search Results
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Item 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 p38γ and p38δ regulate postnatal cardiac metabolism through glycogen synthase 1(PLoS Biology, 2021) Santamans, Ayelén M.; Montalvo-Romeral, Valle; Mora, Alfonso; Lopez, Juan Antonio; González-Romero, Francisco; Jimenez-Blasco, Daniel; Rodríguez, Elena; Pintor-Chocano, Aránzazu; Casanueva-Benítez, Cristina; Acín-Pérez, Rebeca; Leiva-Vega, Luis; Duran, Jordi; Guinovart, Joan J.; Jiménez-Borreguero, Jesús; Aspichueta, Patricia; Vázquez, Jesús; González-Terán, Bárbara; Sabio, Guadalupe; Enríquez González, José Antonio; Villalba Orero, María; Bolaños, Juan P.; Rebecca HaeuslerDuring the first weeks of postnatal heart development cardiomyocytes undergo a major adaptive metabolic shift from glycolytic energy production to fatty acid oxidation. This metabolic change is contemporaneous to the up-regulation and activation of the p38γ and p38δ stress-activated protein kinases in the heart. We demonstrate that p38γ/δ contribute to the early postnatal cardiac metabolic switch through inhibitory phosphorylation of glycogen synthase 1 (GYS1) and glycogen metabolism inactivation. Premature induction of p38γ/δ activation in cardiomyocytes of newborn mice results in an early GYS1 phosphorylation and inhibition of cardiac glycogen production, triggering an early metabolic shift that induces a deficit in cardiomyocyte fuel supply, leading to whole-body metabolic deregulation and maladaptive cardiac pathogenesis. Notably, the adverse effects of forced premature cardiac p38γ/δ activation in neonate mice are prevented by maternal diet supplementation of fatty acids during pregnancy and lactation. These results suggest that diet interventions have a potential for treating human cardiac genetic diseases that affect heart metabolism.Item Capillary pruning couples tissue perfusion and oxygenation with cardiomyocyte maturation in the postnatal mouse heart(Frontiers in Cell and Developmental Biology, 2023) Santamaría, Ricardo; Cruz-Caballero, Javier; Gkontra, Polyxeni; Jiménez-Montiel, Alberto; Clemente, Cristina; López,Juan A.; Vázquez, Jesús; Hutloff, Andreas; Lara-Pezzi, Enrique; Arroyo, Alicia G.; Villalba Orero, MaríaIntroduction: Removal of poorly perfused capillaries by pruning contributes to remodeling the microvasculature to optimize oxygen and nutrient delivery. Blood flow drives this process by promoting the intravascular migration of endothelial cells in developing networks, such as in the yolk sac, zebrafish brain or postnatal mouse retina. Methods: In this study, we have implemented innovative tools to recognize capillary pruning in the complex 3D coronary microvasculature of the postnatal mouse heart. We have also experimentally tested the impact of decreasing pruning on the structure and function of this network by altering blood flow with two different vasodilators: losartan and prazosin. Results: Although both drugs reduced capillary pruning, a combination of experiments based on ex vivo imaging, proteomics, electron microscopy and in vivo functional approaches showed that losartan treatment resulted in an inefficient coronary network, reduced myocardial oxygenation and metabolic changes that delayed the arrest of cardiomyocyte proliferation, in contrast to the effects of prazosin, probably due to its concomitant promotion of capillary expansion. Discussion: Our work demonstrates that capillary pruning contributes to proper maturation and function of the heart and that manipulation of blood flow may be a novel strategy to refine the microvasculature and improve tissue perfusion after damage.Item MCJ: A mitochondrial target for cardiac intervention in pulmonary hypertension(2024) Santamans, Ayelén M.; Cicuéndez, Beatriz; Mora, Alfonso; Rajlic, Sanela; Crespo, María; Vo, Paula; Jerome, Madison; Macías, Álvaro; López, Juan Antonio; Rocha, Susana F.; León, Marta; Rodríguez, Elena; Leiva, Luis; Pintor Chocano, Aránzazu; García Lunar, Inés; García-Álvarez, Ana; Hernansanz-Agustín, Pablo; Peinado, Víctor I.; Barberá, Joan Albert; Ibañez, Borja; Vázquez, Jesús; Spinelli, Jessica B.; Daiber, Andreas; Oliver, Eduardo; Sabio, Guadalupe; Villalba Orero, María; Leiva Arjona, María MagdalenaPulmonary hypertension (PH) can affect both pulmonary arterial tree and cardiac function, often leading to right heart failure and death. Despite the urgency, the lack of understanding has limited the development of effective cardiac therapeutic strategies. Our research reveals that MCJ modulates mitochondrial response to chronic hypoxia. MCJ levels elevate under hypoxic conditions, as in lungs of patients affected by COPD, mice exposed to hypoxia, and myocardium from pigs subjected to right ventricular (RV) overload. The absence of MCJ preserves RV function, safeguarding against both cardiac and lung remodeling induced by chronic hypoxia. Cardiac-specific silencing is enough to protect against cardiac dysfunction despite the adverse pulmonary remodeling. Mechanistically, the absence of MCJ triggers a protective preconditioning state mediated by the ROS/mTOR/HIF-1α axis. As a result, it preserves RV systolic function following hypoxia exposure. These discoveries provide a potential avenue to alleviate chronic hypoxia-induced PH, highlighting MCJ as a promising target against this condition.Item 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.