Padrón-Barthe, LauraVillalba Orero, MaríaGómez-Salinero, Jesús M.Rebeca Acín-Pérez, RebecaSara Cogliati, SaraLópez-Olañeta, MarinaOrtiz Sánchez, PaulaBonzón-Kulichenko, ElenaVázquez. JesúsGarcía-Pavía, PabloRosenthal, NadiaEnríquez, José AntonioLara-Pezzi, Enrique2024-01-302024-01-302018-02-13Padrón-Barthe, L., Villalba-Orero, M., Gómez-Salinero, J. M., Acín-Pérez, R., Cogliati, S., López-Olañeta, M., Ortiz-Sánchez, P., Bonzón-Kulichenko, E., Vázquez, J., García-Pavía, P., Rosenthal, N., Enríquez, J. A., & Lara-Pezzi, E. (2018). Activation of Serine One-Carbon Metabolism by Calcineurin Aβ1 Reduces Myocardial Hypertrophy and Improves Ventricular Function. Journal of the American College of Cardiology, 71(6), 654–667. https://doi.org/10.1016/j.jacc.2017.11.067 Copy Download .nbib0735-109710.1016/j.jacc.2017.11.067https://hdl.handle.net/20.500.14352/96280This work was supported by grants from the European Union (CardioNeT-ITN-289600 and CardioNext-608027 to Dr. Lara-Pezzi; Meet-ITN-317433 to Dr. Enríquez; UE0/MCA1108 to Dr. Acín-Pérez), from the Spanish Ministry of Economy and Competitiveness (SAF2015-65722-R and SAF2012-31451 to Dr. Lara-Pezzi; SAF2015-71521-REDC, BFU2013-50448, and SAF2012-32776 to Dr. Enríquez; RyC-2011-07826 to Dr. Acín-Pérez; BIO2012-37926 and BIO2015-67580-P to Dr. Vázquez), from the Spanish Carlos III Institute of Health (CPII14/00027 to Dr. Lara-Pezzi; RD12/0042/066 to Drs. García-Pavía and Lara-Pezzi), from the Regional Government of Madrid (2010-BMD-2321 “Fibroteam” to Dr. Lara-Pezzi; 2011-BMD-2402 “Mitolab” to Dr. Enríquez) and the FIS-ISCIII (PRB2-IPT13/0001 and RD12/0042/0056-RIC-RETICS to Dr. Vázquez). This work was also supported by the Plan Estatal de I+D+I 2013-2016–European Regional Development Fund (FEDER) “A way of making Europe,” Spain. The CNIC is supported by the Spanish Ministry of Economy and Competitiveness and by the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). Drs. Vázquez and García-Pavía have served as consultants for VL39. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Padrón-Barthe, Villalba-Orero, and Gómez-Salinero contributed equally to this work and are joint first authors. Robyn Shaw, MD, PhD, served as Guest Editor for this paper.Background: 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 approachengAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/journal articlehttps://www.sciencedirect.com/science/article/pii/S0735109717418705?via%3Dihub29420962open access61Cardiac functionCell signalingHypertrophyMetabolism.Ciencias Biomédicas32 Ciencias Médicas