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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.
Antioxid Redox Signal. 2013 Jan 01; 18(1):5-18.AR

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+Show Affiliations

INSERM, UMR 1048, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22738191

Citation

Villeneuve, Christelle, et al. "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." Antioxidants & Redox Signaling, vol. 18, no. 1, 2013, pp. 5-18.
Villeneuve C, Guilbeau-Frugier C, Sicard P, et al. 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. Antioxid Redox Signal. 2013;18(1):5-18.
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, M. B., Parini, A., & Mialet-Perez, J. (2013). 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. Antioxidants & Redox Signaling, 18(1), 5-18. https://doi.org/10.1089/ars.2011.4373
Villeneuve C, et al. 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. Antioxid Redox Signal. 2013 Jan 1;18(1):5-18. PubMed PMID: 22738191.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Villeneuve,Christelle, AU - Guilbeau-Frugier,Céline, AU - Sicard,Pierre, AU - Lairez,Olivier, AU - Ordener,Catherine, AU - Duparc,Thibaut, AU - De Paulis,Damien, AU - Couderc,Bettina, AU - Spreux-Varoquaux,Odile, AU - Tortosa,Florence, AU - Garnier,Anne, AU - Knauf,Claude, AU - Valet,Philippe, AU - Borchi,Elisabetta, AU - Nediani,Chiara, AU - Gharib,Abdallah, AU - Ovize,Michel, AU - Delisle,Marie-Bernadette, AU - Parini,Angelo, AU - Mialet-Perez,Jeanne, Y1 - 2012/08/10/ PY - 2012/6/29/entrez PY - 2012/6/29/pubmed PY - 2013/5/15/medline SP - 5 EP - 18 JF - Antioxidants & redox signaling JO - Antioxid. Redox Signal. VL - 18 IS - 1 N2 - 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. SN - 1557-7716 UR - https://www.unboundmedicine.com/medline/citation/22738191/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_ L2 - https://www.liebertpub.com/doi/full/10.1089/ars.2011.4373?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -