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p53-PGC-1α Pathway Mediates Oxidative Mitochondrial Damage and Cardiomyocyte Necrosis Induced by Monoamine Oxidase-A Upregulation: Role in Chronic Left Ventricular Dysfunction in Mice.
Villeneuve C., Guilbeau-Frugier C., Sicard P., Lairez O., Ordener C., Duparc T., De Paulis D., Couderc B., Spreux-Varoquaux O., Tortosa F. et al
Antioxidants and Redox Signaling (2012) epub ahead of print - http://www.hal.inserm.fr/inserm-00755534
p53-PGC-1α Pathway Mediates Oxidative Mitochondrial Damage and Cardiomyocyte Necrosis Induced by Monoamine Oxidase-A Upregulation: Role in Chronic Left Ventricular Dysfunction in Mice.
Christelle Villeneuve1, 2, Céline Guilbeau-Frugier1, 2, Pierre Sicard1, 2, Olivier Lairez1, 2, Catherine Ordener1, 2, Thibaut Duparc1, 2, Damien De Paulis3, 4, Bettina Couderc2, Odile Spreux-Varoquaux5, Florence Tortosa1, 2, Anne Garnier6, Claude Knauf1, 2, Philippe Valet1, 2, Elisabetta Borchi7, Chiara Nediani7, Abdallah Gharib3, 4, Michel Ovize4, Marie-Bernadette Delisle1, 2, Angelo Parini () 1, 2, Jeanne Mialet-Perez1, 2
1 :  I2MC - Institut des Maladies Métaboliques et Cardiovasculaires
INSERM : U1048 – Université Paul Sabatier (UPS) - Toulouse III – Hôpital de Rangueil
1 avenue du Prof Jean Poulhes - BP 84225 - 31432 Toulouse Cedex 4
2 :  Institut Claudius Regaud
CRLCC Institut Claudius Regaud
3 :  Service de cardiologie
Hôpital Louis Pradel
69677 Bron
4 :  Cardioprotection
INSERM : U886 – Université Claude Bernard - Lyon I
Domaine rockefeller 8, avenue rockefeller laboratoire de physiologie-lyon nord 69373 LYON CEDEX 08
5 :  UVSQ - Université Versailles Saint-Quentin en Yvelines
Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)
6 :  Signalisation et physiopathologie cardiaque
INSERM : U769 – IFR141 – Université Paris XI - Paris Sud
Faculte de Pharmacie 5, Rue Jean-Baptiste Clement 92296 Chatenay Malabry Cedex
7 :  Department of Biochemical Sciences
University of Florence
Abstract Aims: Oxidative stress and mitochondrial dysfunction participate together in the development of heart failure (HF). mRNA levels of monoamine oxidase-A (MAO-A), a mitochondrial enzyme that produces hydrogen peroxide (H(2)O(2)), increase in several models of cardiomyopathies. Therefore, we hypothesized that an increase in cardiac MAO-A could cause oxidative stress and mitochondrial damage, leading to cardiac dysfunction. In the present study, we evaluated the consequences of cardiac MAO-A augmentation on chronic oxidative damage, cardiomyocyte survival, and heart function, and identified the intracellular pathways involved. Results: We generated transgenic (Tg) mice with cardiac-specific MAO-A overexpression. Tg mice displayed cardiac MAO-A activity levels similar to those found in HF and aging. As expected, Tg mice showed a significant decrease in the cardiac amounts of the MAO-A substrates serotonin and norepinephrine. This was associated with enhanced H(2)O(2) generation in situ and mitochondrial DNA oxidation. As a consequence, MAO-A Tg mice demonstrated progressive loss of cardiomyocytes by necrosis and ventricular failure, which were prevented by chronic treatment with the MAO-A inhibitor clorgyline and the antioxidant N-acetyl-cystein. Interestingly, Tg hearts exhibited p53 accumulation and downregulation of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a master regulator of mitochondrial function. This was concomitant with cardiac mitochondrial ultrastructural defects and ATP depletion. In vitro, MAO-A adenovirus transduction of neonatal cardiomyocytes mimicked the results in MAO-A Tg mice, triggering oxidative stress-dependent p53 activation, leading to PGC-1α downregulation, mitochondrial impairment, and cardiomyocyte necrosis. Innovation and Conclusion: We provide the first evidence that MAO-A upregulation in the heart causes oxidative mitochondrial damage, p53-dependent repression of PGC-1α, cardiomyocyte necrosis, and chronic ventricular dysfunction. Antioxid. Redox Signal. 00, 000-000.
Sciences du Vivant/Biologie cellulaire

Articles dans des revues avec comité de lecture
Antioxidants and Redox Signaling (Antioxid Redox Signal)
Publisher Mary Ann Liebert
ISSN 1523-0864 
epub ahead of print