Serotonin and angiotensin receptors in cardiac fibroblasts coregulate adrenergic-dependent cardiac hypertrophy.
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 AT(1)Rs 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 AT(1) 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.
Jaffré
Fabrice
F
Institut National de Santé et de Recherche Médicale, U839, Paris, France.
Bonnin
Philippe
P
Callebert
Jacques
J
Debbabi
Haythem
H
Setola
Vincent
V
Doly
Stéphane
S
Monassier
Laurent
L
Mettauer
Bertrand
B
Blaxall
Burns C
BC
Launay
Jean-Marie
JM
Maroteaux
Luc
L
D000328:Adult; D000804:Angiotensin II / Q000172:deficiency / Q000502:physiology / Q000633:toxicity; D000818:Animals; D002478:Cells, Cultured / Q000378:metabolism; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D066246:ErbB Receptors / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology*; D006333:Heart Failure / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D007545:Isoproterenol / Q000633:toxicity; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism; D009638:Norepinephrine / Q000502:physiology; D025941:Protein Interaction Mapping; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology*; D044403:Receptor, Serotonin, 5-HT2B / Q000502:physiology*; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000502:physiology
D016207:Cytokines; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D044140:Receptor, Angiotensin, Type 1; D044403:Receptor, Serotonin, 5-HT2B; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D000804:Angiotensin II; D066246:ErbB Receptors; D019061:src-Family Kinases; D007545:Isoproterenol; D009638:Norepinephrine