Document Detail

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.
MedLine Citation:
PMID:  22738191     Owner:  NLM     Status:  MEDLINE    
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.
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
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-08-10
Journal Detail:
Title:  Antioxidants & redox signaling     Volume:  18     ISSN:  1557-7716     ISO Abbreviation:  Antioxid. Redox Signal.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2012-12-03     Completed Date:  2013-05-13     Revised Date:  2014-01-10    
Medline Journal Info:
Nlm Unique ID:  100888899     Medline TA:  Antioxid Redox Signal     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5-18     Citation Subset:  IM    
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MeSH Terms
Cardiomyopathy, Dilated / enzymology
Cells, Cultured
Chronic Disease
Enzyme Induction
Heart Ventricles / enzymology,  pathology
Hypertrophy, Left Ventricular / enzymology
Mice, Inbred C57BL
Mice, Transgenic
Mitochondria, Heart / enzymology*
Monoamine Oxidase / genetics,  metabolism*
Myocytes, Cardiac / metabolism,  pathology*
Necrosis / enzymology*
Oxidative Stress
Rats, Sprague-Dawley
Trans-Activators / metabolism*
Transcription Factors
Tumor Suppressor Protein p53 / metabolism*
Ventricular Dysfunction, Left / enzymology*,  pathology
Reg. No./Substance:
0/Ppargc1a protein, mouse; 0/Trans-Activators; 0/Transcription Factors; 0/Tumor Suppressor Protein p53; EC Oxidase

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