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(Circulation. 2005;112:3297-3305.)
© 2005 American Heart Association, Inc.

Heart Failure

Oxidative Stress by Monoamine Oxidase Mediates Receptor-Independent Cardiomyocyte Apoptosis by Serotonin and Postischemic Myocardial Injury

Pascale Bianchi, PhD; Oxana Kunduzova, PhD; Emanuela Masini, MD; Claudie Cambon, PhD; Daniele Bani, MD; Laura Raimondi, PharmD; Marie-Helene Seguelas, BSc; Silvia Nistri, PhD; Wilson Colucci, MD; Nathalie Leducq, PhD; Angelo Parini, MD, PhD

From INSERM U388, Toulouse, France (P.B., O.K., C.C., M.-H.S., A.P.); Department of Preclinical and Clinical Pharmacology, Department of Anatomy, Histology and Forensic Medicine, University of Florence, Florence, Italy (L.M., D.B., L.R., S.N.); Boston University Medical Center, Boston, Mass (W.C.); and Cardiovascular-Thrombosis Research Department, Sanofi-Synthélabo Research, Toulouse, France (N.L.).

Correspondence to Angelo Parini, MD, PhD, IRF31, BP 84225, INSERM U388, 31432 Toulouse Cedex 4, France. E-mail parini{at}toulouse.inserm.fr

Received December 8, 2004; revision received August 23, 2005; accepted August 24, 2005.

Background— Serotonin (5-hydroxytryptamine [5-HT]), released by activated platelets during cardiac ischemia, is metabolized by the mitochondrial enzyme monoamine oxidase A (MAO-A). Because hydrogen peroxide is one of the byproducts of 5-HT degradation by MAO-A, we investigated the potential role of reactive oxygen species generated by MAOs in 5-HT-dependent cardiomyocyte death and post-ischemia-reperfusion cardiac damage.

Methods and Results— Treatment of isolated adult rat cardiomyocytes with 5-HT induced intracellular oxidative stress and cell apoptosis. The apoptotic cascade triggered by 5-HT involves release of cytochrome c, upregulation of proapoptotic Bax protein, and downregulation of antiapoptotic Bcl-2 protein. These effects were prevented by inhibition of amine transporter or MAO, antioxidants, or iron chelation. In contrast, cardiomyocyte apoptosis was only slightly affected by the 5-HT_2B receptor antagonist SB 206553. In vivo, inhibition of MAO-A largely reduced myocardial ultrastructural damage induced by 30 minutes of ischemia followed by 60 minutes of reperfusion in the rat heart. Cardioprotective effects of MAO inhibitors were associated with the prevention of postischemic oxidative stress, neutrophil accumulation, and mitochondrial-dependent cell death and were not reverted by SB 206553. Administration of MAO-A inhibitors during ischemia was still effective in preventing cardiac damage.

Conclusions— Our results supply the first direct evidence that oxidative stress induced by MAO is responsible for receptor-independent apoptotic effects of 5-HT in cardiomyocytes and postischemic myocardial injury. These findings provide new insight into the mechanisms of 5-HT action in the heart and may constitute the basis for novel therapies.

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