Activation of Serine One-Carbon Metabolism by Calcineurin Aβ1 Reduces Myocardial Hypertrophy and Improves Ventricular Function

Laura Padrón-Barthe, María Villalba-Orero, Jesús M. Gómez-Salinero, Rebeca Acín-Pérez, Sara Cogliati, Marina López-Olañeta, Paula Ortiz-Sánchez, Elena Bonzón-Kulichenko, Jesús Vázquez, Pablo García-Pavía, Nadia Rosenthal, José Antonio Enríquez, Enrique Lara-Pezzi

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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 approaches.

Original languageEnglish
Pages (from-to)654-667
Number of pages14
JournalJournal of the American College of Cardiology
Volume71
Issue number6
DOIs
Publication statusPublished - 13 Feb 2018
Externally publishedYes

Keywords

  • cardiac function
  • cell signaling
  • hypertrophy
  • metabolism

Cite this

Padrón-Barthe, L., Villalba-Orero, M., Gómez-Salinero, J. M., Acín-Pérez, R., Cogliati, S., López-Olañeta, M., ... 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
Padrón-Barthe, Laura ; Villalba-Orero, María ; Gómez-Salinero, Jesús M. ; Acín-Pérez, Rebeca ; Cogliati, Sara ; López-Olañeta, Marina ; Ortiz-Sánchez, Paula ; Bonzón-Kulichenko, Elena ; Vázquez, Jesús ; García-Pavía, Pablo ; Rosenthal, Nadia ; Enríquez, José Antonio ; Lara-Pezzi, Enrique. / Activation of Serine One-Carbon Metabolism by Calcineurin Aβ1 Reduces Myocardial Hypertrophy and Improves Ventricular Function. In: Journal of the American College of Cardiology. 2018 ; Vol. 71, No. 6. pp. 654-667.
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abstract = "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 approaches.",
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Padrón-Barthe, L, Villalba-Orero, M, Gómez-Salinero, JM, Acín-Pérez, R, Cogliati, S, López-Olañeta, M, Ortiz-Sánchez, P, Bonzón-Kulichenko, E, Vázquez, J, García-Pavía, P, Rosenthal, N, Enríquez, JA & 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, vol. 71, no. 6, pp. 654-667. https://doi.org/10.1016/j.jacc.2017.11.067

Activation of Serine One-Carbon Metabolism by Calcineurin Aβ1 Reduces Myocardial Hypertrophy and Improves Ventricular Function. / Padrón-Barthe, Laura; Villalba-Orero, María; Gómez-Salinero, Jesús M.; Acín-Pérez, Rebeca; Cogliati, Sara; López-Olañeta, Marina; Ortiz-Sánchez, Paula; Bonzón-Kulichenko, Elena; Vázquez, Jesús; García-Pavía, Pablo; Rosenthal, Nadia; Enríquez, José Antonio; Lara-Pezzi, Enrique.

In: Journal of the American College of Cardiology, Vol. 71, No. 6, 13.02.2018, p. 654-667.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Activation of Serine One-Carbon Metabolism by Calcineurin Aβ1 Reduces Myocardial Hypertrophy and Improves Ventricular Function

AU - Padrón-Barthe, Laura

AU - Villalba-Orero, María

AU - Gómez-Salinero, Jesús M.

AU - Acín-Pérez, Rebeca

AU - Cogliati, Sara

AU - López-Olañeta, Marina

AU - Ortiz-Sánchez, Paula

AU - Bonzón-Kulichenko, Elena

AU - Vázquez, Jesús

AU - García-Pavía, Pablo

AU - Rosenthal, Nadia

AU - Enríquez, José Antonio

AU - Lara-Pezzi, Enrique

PY - 2018/2/13

Y1 - 2018/2/13

N2 - 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 approaches.

AB - 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 approaches.

KW - cardiac function

KW - cell signaling

KW - hypertrophy

KW - metabolism

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U2 - 10.1016/j.jacc.2017.11.067

DO - 10.1016/j.jacc.2017.11.067

M3 - Article

VL - 71

SP - 654

EP - 667

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

SN - 0735-1097

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ER -