A new hypertrophic mechanism of serotonin in cardiac myocytes: receptor-independent ROS generation.

TitleA new hypertrophic mechanism of serotonin in cardiac myocytes: receptor-independent ROS generation.
Publication TypeJournal Article
Year of Publication2005
AuthorsBianchi, P, Pimentel, DR, Murphy, MP, Colucci, WS, Parini, A
JournalFASEB J
Volume19
Issue6
Pagination641-3
Date Published2005 Apr
ISSN1530-6860
KeywordsAdrenergic Uptake Inhibitors, Animals, Catalase, Cells, Cultured, Enzyme Activation, Flavonoids, Gene Expression, Glutathione, Hydrogen Peroxide, Hypertrophy, Imipramine, Male, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinase Kinases, Monoamine Oxidase, Monoamine Oxidase Inhibitors, Myocytes, Cardiac, Oxidation-Reduction, Oxidative Stress, Pargyline, Phosphorylation, Rats, Rats, Sprague-Dawley, Reactive Oxygen Species, Serotonin, Transfection
Abstract

Reactive oxygen species (ROS) play a critical role in cardiac hypertrophy. We have recently shown that the serotonin-degrading enzyme monoamine oxidase A (MAO A) is an important source of hydrogen peroxide in rat heart. In the present study, we investigated the potential role of hydrogen peroxide generated by MAO A in cardiomyocyte hypertrophy by serotonin. Serotonin (5 microM, 48 h) induced hypertrophy in cultured adult rat ventricular myocytes, as reflected by increased 3H-leucine incorporation (+43%, P<0.001) and total protein content (+22%, P<0.001). Serotonin also increased intracellular hydrogen peroxide and oxidative stress production, measured respectively by DCF fluorescence intensity and GSH/GSSG ratio, and promoted ERK1/2 phosphorylation (P<0.001). Serotonin effects were only partially inhibited by the 5-HT2B receptor antagonist SB 206553. In contrast, they were extensively (>80%) prevented by the amine uptake inhibitor imipramine, the MAO inhibitor pargyline and the MEK inhibitor PD 98059. Cardiomyocyte hypertrophy and ERK activation were also inhibited by decreasing intracellular ROS by adenoviral overexpression of catalase or cardiomyocytes treatment with the iron chelator deferoxamine. These data suggest that part of cardiac hypertrophic effect of serotonin requires hydrogen peroxide production by MAO A and ERK1/2 activation. This newly recognized, receptor-independent mechanism of serotonin may contribute to myocardial remodeling and failure.

DOI10.1096/fj.04-2518fje
Alternate JournalFASEB J.
Citation Key10.1096/fj.04-2518fje
PubMed ID15703274
Grant ListHL20612 / HL / NHLBI NIH HHS / United States
HL61639 / HL / NHLBI NIH HHS / United States