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p53-PGC-1alpha 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; Garnier A; Knauf C; Valet P; Borchi E; Nediani C; Gharib A; Ovize M; Delisle MB; Parini A; Mialet-Perez JAntioxid Redox Signal 2013[Jan]; 18 (1): 5-18AIMS: 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-gamma coactivator-1alpha (PGC-1alpha), 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-1alpha 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-1alpha, cardiomyocyte necrosis, and chronic ventricular dysfunction.|Animals[MESH]|Cardiomyopathy, Dilated/enzymology[MESH]|Cells, Cultured[MESH]|Chronic Disease[MESH]|Enzyme Induction[MESH]|Fibrosis[MESH]|Heart Ventricles/enzymology/pathology[MESH]|Hypertrophy, Left Ventricular/enzymology[MESH]|Male[MESH]|Mice[MESH]|Mice, Inbred C57BL[MESH]|Mice, Transgenic[MESH]|Mitochondria, Heart/*enzymology[MESH]|Monoamine Oxidase/genetics/*metabolism[MESH]|Myocytes, Cardiac/metabolism/*pathology[MESH]|Necrosis/*enzymology[MESH]|Oxidation-Reduction[MESH]|Oxidative Stress[MESH]|Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha[MESH]|Rats[MESH]|Rats, Sprague-Dawley[MESH]|Trans-Activators/*metabolism[MESH]|Transcription Factors[MESH]|Tumor Suppressor Protein p53/*metabolism[MESH]|Up-Regulation[MESH]|Ventricular Dysfunction, Left/*enzymology/pathology[MESH] |
