Monoamine oxidase a-mediated enhanced catabolism of norepinephrine contributes to adverse remodeling and pump failure in hearts with pressure overload

Nina Kaludercic, Eiki Takimoto, Takahiro Nagayama, Ning Feng, Edwin W. Lai, Djahida Bedja, Kevin Chen, Kathleen L. Gabrielson, Randy D. Blakely, Jean C. Shih, Karel Pacak, David A. Kass, Fabio Di Lisa, Nazareno Paolocci*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

190 Citations (Scopus)
28 Downloads (Pure)

Abstract

RATIONALE: Monoamine oxidases (MAOs) are mitochondrial enzymes that catabolize prohypertrophic neurotransmitters, such as norepinephrine and serotonin, generating hydrogen peroxide. Because excess reactive oxygen species and catecholamines are major contributors to the pathophysiology of congestive heart failure, MAOs could play an important role in this process. OBJECTIVE: Here, we investigated the role of MAO-A in maladaptive hypertrophy and heart failure. METHODS AND RESULTS: We report that MAO-A activity is triggered in isolated neonatal and adult myocytes on stimulation with norepinephrine, followed by increase in cell size, reactive oxygen species production, and signs of maladaptive hypertrophy. All of these in vitro changes occur, in part, independently from α-and β-adrenergic receptor-operated signaling and are inhibited by the specific MAO-A inhibitor clorgyline. In mice with left ventricular dilation and pump failure attributable to pressure overload, norepinephrine catabolism by MAO-A is increased accompanied by exacerbated oxidative stress. MAO-A inhibition prevents these changes, and also reverses fetal gene reprogramming, metalloproteinase and caspase-3 activation, as well as myocardial apoptosis. The specific role of MAO-A was further tested in mice expressing a dominant-negative MAO-A (MAO-Aneo), which were more protected against pressure overload than their wild-type littermates. CONCLUSIONS: In addition to adrenergic receptor-dependent mechanisms, enhanced MAO-A activity coupled with increased intramyocardial norepinephrine availability results in augmented reactive oxygen species generation, contributing to maladaptive remodeling and left ventricular dysfunction in hearts subjected to chronic stress.

Original languageEnglish
Pages (from-to)193-202
Number of pages10
JournalCirculation Research
Volume106
Issue number1
DOIs
Publication statusPublished - 2010
Externally publishedYes

Bibliographical note

Copyright the Publisher 2009. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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