Published Online
on June 30, 2008

A more recent version of this article appeared on August 1, 2008

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Submitted on November 21, 2007
Revised on December 10, 2007

Serotonin 5-HT_2B Receptor Blockade Prevents Reactive Oxygen Species–Induced Cardiac Hypertrophy in Mice

Laurent Monassier^*; Marc-André Laplante; Fabrice Jaffré; Pascal Bousquet; Luc Maroteaux; and Jacques de Champlain

From the Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire (L. Monassier, P.B.), INSERM, U-715, Faculté de Médecine, Strasbourg, France; Département de Physiologie (M-A.L., J.d.C.), Faculté de Médecine, Université de Montréal and Laboratoire de Recherche sur le Système Nerveux Autonome, Institut de Recherche Clinique, Montréal, Quebec, Canada; and INSERM (F.J., L. Maroteaux), U-389, Université Pierre et Marie Curie, Institut du Fer à Moulin, Paris, France.

^* To whom correspondence should be addressed. E-mail: laurent.monassier{at}medecine.u-strasbg.fr.

Abstract—We established previously that 5-HT_2B receptors are involved in cardiac hypertrophy through the regulation of hypertrophic cytokines in cardiac fibroblasts. Moreover, the generation of reactive oxygen species and tumor necrosis factor- through the activation of reduced nicotinamide-adenine dinucleotide phosphate [NAD(P)H] oxidase has been implicated in cardiac hypertrophy. In this study, we investigated whether 5-HT_2B receptors could be involved in the development of cardiac hypertrophy associated with superoxide anion production. Therefore, we measured the effects of serotonergic 5-HT_2B receptor blockade on left-ventricular superoxide anion generation in 2 established pharmacological models of cardiac hypertrophy, ie, angiotensin II and isoproterenol infusions in mice. Angiotensin II infusion for 14 days increased superoxide anion concentration (+32%), NAD(P)H oxidase maximal activity (+84%), and p47^phox NAD(P)H oxidase subunit expression in the left ventricle together with hypertension (+37 mm Hg) and cardiac hypertrophy (+17% for heart weight:body weight). The 5-HT_2B receptor blockade by a selective antagonist (SB215505) prevented the increase in cardiac superoxide generation and hypertrophy. Similarly, infusion for 5 days of isoproterenol increased left-ventricular NAD(P)H oxidase activity (+48%) and cardiac hypertrophy (+31%) that were prevented by the 5-HT_2B receptor blockade. Finally, in the primary culture of left-ventricular cardiac fibroblasts, angiotensin II and isoproterenol stimulated NAD(P)H oxidase activity. This activation was prevented by SB215505. These findings suggest that the 5-HT_2B receptor may represent a new target to reduce cardiac hypertrophy and oxidative stress. Its blockade affects both angiotensin II and -adrenergic trophic responses without significant hemodynamic alteration.

Key words: 5-HT_2B • NAD(P)H oxidase • superoxide anion • angiotensin • adrenergic • cardiac • hypertrophy

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