Document Type
Article
Publication Date
2-13-2018
JAX Source
J Am Coll Cardiol 2018 Feb 13; 71(6):654-667
Volume
71
Issue
6
First Page
654
Last Page
667
ISSN
1558-3597
PMID
29420962
DOI
https://doi.org/10.1016/j.jacc.2017.11.067
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.
J Am Coll Cardiol 2018 Feb 13; 71(6):654-667
Recommended Citation
Padrón-Barthe L,
Villalba-Orero M,
Gómez-Salinero J,
Acín-Pérez R,
Cogliati S,
López-Olañeta M,
Ortiz-Sánchez P,
Bonzón-Kulichenko E,
Vázquez J,
García-Pavía P,
Rosenthal N,
Enríquez J,
Lara-Pezzi E.
Activation of Serine One-Carbon Metabolism by Calcineurin Aβ1 Reduces Myocardial Hypertrophy and Improves Ventricular Function. J Am Coll Cardiol 2018 Feb 13; 71(6):654-667
Comments
Open access Under a Creative Commons license.