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.

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.

• Authors: Christelle Villeneuve, Céline Guilbeau-Frugier, Pierre Sicard, Olivier Lairez, Catherine Ordener, Thibaut Duparc, Damien De Paulis, Bettina Couderc, Odile Spreux-Varoquaux, Florence Tortosa, Anne Garnier, Claude Knauf, Philippe Valet, Elisabetta Borchi, Chiara Nediani, Abdallah Gharib, Michel Ovize, Marie-Bernadette Delisle, Angelo Parini, Jeanne Mialet-Perez
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) Vol. 18 Issue 1 Pg. 5-18 (Jan 01 2013) ISSN: 1557-7716 [Electronic] United States
• PMID: 22738191 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Ppargc1a protein, mouse
• Trans-Activators
• Transcription Factors
• Tumor Suppressor Protein p53
• Monoamine Oxidase

Topics

• Animals
• Cardiomyopathy, Dilated (enzymology)
• Cells, Cultured
• Chronic Disease
• Enzyme Induction
• Fibrosis
• Heart Ventricles (enzymology, pathology)
• Hypertrophy, Left Ventricular (enzymology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Mitochondria, Heart (enzymology)
• Monoamine Oxidase (genetics, metabolism)
• Myocytes, Cardiac (metabolism, pathology)
• Necrosis (enzymology)
• Oxidation-Reduction
• Oxidative Stress
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Rats
• Rats, Sprague-Dawley
• Trans-Activators (metabolism)
• Transcription Factors
• Tumor Suppressor Protein p53 (metabolism)
• Up-Regulation
• Ventricular Dysfunction, Left (enzymology, pathology)