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(Circulation Research. 2009;104:113.)
© 2009 American Heart Association, Inc.

Integrative Physiology

Serotonin and Angiotensin Receptors in Cardiac Fibroblasts Coregulate Adrenergic-Dependent Cardiac Hypertrophy

Fabrice Jaffré, Philippe Bonnin, Jacques Callebert, Haythem Debbabi, Vincent Setola, Stéphane Doly, Laurent Monassier, Bertrand Mettauer, Burns C. Blaxall, Jean-Marie Launay, Luc Maroteaux

From Institut National de la Santé et de la Recherche Médicale, U839 (F.J., V.S., S.D., L.M.), Paris, France; Unité Mixte de Recherche S0839 (F.J., V.S., S.D., L.M.), Université Pierre et Marie Curie Paris 6, France; Institut du Fer à Moulin (F.J., V.S., S.D., L.M.), Paris, France; Service de Physiologie–Explorations Fonctionnelles (P.B., H.D.), Assistance Publique–Hôpitaux de Paris, Hôpital Lariboisière, Université Denis Diderot Paris 7, France; Institut National de la Santé et de la Recherche Médicale, U689 (P.B., H.D.), Centre de Recherche Cardiovasculaire, Hôpital Lariboisière, Paris, France; Service de Biochimie (J.C., J.-M.L.), Assistance Publique–Hôpitaux de Paris, Hôpital Lariboisière, France; EA3621 (J.C., J.-M.L.), IFR71, Paris, France; Institut National de la Santé et de la Recherche Médicale, U715 (L.M.), Faculté de Médecine, Strasbourg, France; Service de Cardiologie (B.M.), Hôpital de Colmar, France; and Cardiovascular Research Institute (B.C.B.), Aab Cardiovascular Institute, University of Rochester School of Medicine, New York.

Correspondence to Luc Maroteaux INSERM, U839, Institut du Fer à Moulin, 17 rue du Fer à Moulin, 75005 Paris, France. E-mail luc.maroteaux{at}chups.jussieu.fr

By mimicking sympathetic stimulation in vivo, we previously reported that mice globally lacking serotonin 5-HT_2B receptors did not develop isoproterenol-induced left ventricular hypertrophy. However, the exact cardiac cell type(s) expressing 5-HT_2B receptors (cardiomyocytes versus noncardiomyocytes) involved in pathological heart hypertrophy was never addressed in vivo. We report here that mice expressing the 5-HT_2B receptor solely in cardiomyocytes, like global 5-HT_2B receptor–null mice, are resistant to isoproterenol-induced cardiac hypertrophy and dysfunction, as well as to isoproterenol-induced increases in cytokine plasma-levels. These data reveal a key role of noncardiomyocytes in isoproterenol-induced hypertrophy in vivo. Interestingly, we show that primary cultures of angiotensinogen null adult cardiac fibroblasts are releasing cytokines on stimulation with either angiotensin II or serotonin, but not in response to isoproterenol stimulation, demonstrating a critical role of angiotensinogen in adrenergic-dependent cytokine production. We then show a functional interdependence between AT₁Rs and 5-HT_2B receptors in fibroblasts by revealing a transinhibition mechanism that may involve heterodimeric receptor complexes. Both serotonin- and angiotensin II–dependent cytokine production occur via a Src/heparin-binding epidermal growth factor–dependent transactivation of epidermal growth factor receptors in cardiac fibroblasts, supporting a common signaling pathway. Finally, we demonstrate that 5-HT_2B receptors are overexpressed in hearts from patients with congestive heart failure, this overexpression being positively correlated with cytokine and norepinephrine plasma levels. Collectively, these results reveal for the first time that interactions between AT₁ and 5-HT_2B receptors coexpressed by noncardiomyocytes are limiting key events in adrenergic agonist-induced, angiotensin-dependent cardiac hypertrophy. Accordingly, antagonists of 5-HT_2B receptors might represent novel therapeutics for sympathetic overstimulation-dependent heart failure.

Key Words: fibroblast • heart failure • hypertrophy • interleukins • sympathetic nervous system

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