Published online before print November 20, 2008, doi: 10.1161/CIRCRESAHA.108.180976
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Submitted on June 6, 2008
Revised on October 15, 2008
Accepted on November 6, 2008
Serotonin and Angiotensin Receptors in Cardiac Fibroblasts Coregulate Adrenergic-Dependent Cardiac Hypertrophy
Fabrice Jaffré ;
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.), University of Rochester Medical Center, New York.
* To whom correspondence should be addressed. E-mail: luc.maroteaux{at}chups.jussieu.fr.
By mimicking sympathetic stimulation in vivo, we previously reported that mice globally lacking serotonin (5-HT2B) receptors (5-HT2BRs) did not develop isoproterenol-induced left ventricular hypertrophy. However, the exact cardiac cell type(s) expressing 5-HT2BRs (cardiomyocytes versus noncardiomyocytes) involved in pathological heart hypertrophy was never addressed in vivo. We report here that mice expressing the 5-HT2B receptor solely in cardiomyocytes, like global 5-HT2B 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-HT2BRs 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-HT2B receptors are overexpressed in hearts from patients with congestive heart failure, this overexpression being positively correlated with cytokine and catecholamine plasma levels. Collectively, these results reveal for the first time that interactions between AT1 and 5-HT2B receptors coexpressed by noncardiomyocytes are limiting key events in adrenergic agonist-induced, angiotensin-dependent cardiac hypertrophy. Accordingly, antagonists of 5-HT2B receptors might represent novel therapeutics for sympathetic overstimulation-dependent heart failure.
Key words: fibroblast • heart failure • hypertrophy • interleukins • sympathetic nervous system
Related Article:
- Serotonin 5-HT2B Receptor in Cardiac Fibroblast Contributes to Cardiac Hypertrophy: A New Therapeutic Target for Heart Failure?
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