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.
OBJECTIVE
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.


CONCLUSIONS
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.
INSERM, UMR 1048, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France.
Christelle
C
Villeneuve
Céline
C
Guilbeau-Frugier
Pierre
P
Sicard
Olivier
O
Lairez
Catherine
C
Ordener
Thibaut
T
Duparc
Damien
D
De Paulis
Bettina
B
Couderc
Odile
O
Spreux-Varoquaux
Florence
F
Tortosa
Anne
A
Garnier
Claude
C
Knauf
Philippe
P
Valet
Elisabetta
E
Borchi
Chiara
C
Nediani
Abdallah
A
Gharib
Michel
M
Ovize
Marie-Bernadette
MB
Delisle
Angelo
A
Parini
Jeanne
J
Mialet-Perez
D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000201:enzymology; D002478:Cells, Cultured; D002908:Chronic Disease; D004790:Enzyme Induction; D005355:Fibrosis; D006352:Heart Ventricles / Q000201:enzymology / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000201:enzymology*; D008995:Monoamine Oxidase / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D009336:Necrosis / Q000201:enzymology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051381:Rats; D017207:Rats, Sprague-Dawley; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation; D018487:Ventricular Dysfunction, Left / Q000201:enzymology* / Q000473:pathology
D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D008995:Monoamine Oxidase