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PMID:19023134

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Citation

Jaffré, F, Bonnin, P, Callebert, J, Debbabi, H, Setola, V, Doly, S, Monassier, L, Mettauer, B, Blaxall, BC, Launay, JM and Maroteaux, L (2009) Serotonin and angiotensin receptors in cardiac fibroblasts coregulate adrenergic-dependent cardiac hypertrophy. Circ. Res. 104:113-23

Abstract

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.

Links

PubMed Online version:10.1161/CIRCRESAHA.108.180976

Keywords

Adult; Angiotensin II/deficiency; Angiotensin II/physiology; Angiotensin II/toxicity; Animals; Cells, Cultured/metabolism; Cells, Cultured/secretion; Cytokines/blood; Cytokines/secretion; Female; Fibroblasts/drug effects; Fibroblasts/physiology; Heart Failure/chemically induced; Heart Failure/drug therapy; Heart Failure/pathology; Heart Failure/physiopathology; Humans; Hypertrophy, Left Ventricular/chemically induced; Hypertrophy, Left Ventricular/physiopathology; Hypertrophy, Left Ventricular/prevention & control; Intercellular Signaling Peptides and Proteins/physiology; Isoproterenol/toxicity; Male; Mice; Mice, Knockout; Mice, Transgenic; Middle Aged; Myocardium/metabolism; Myocardium/pathology; Myocytes, Cardiac/metabolism; Norepinephrine/physiology; Protein Interaction Mapping; Receptor, Angiotensin, Type 1/physiology; Receptor, Epidermal Growth Factor/physiology; Receptor, Serotonin, 5-HT2B/physiology; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists/therapeutic use; Signal Transduction/drug effects; src-Family Kinases/antagonists & inhibitors; src-Family Kinases/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:ANGT

involved_in

GO:0001819: positive regulation of cytokine production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:AGTRA

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P30994

F

Seeded From UniProt

complete

RAT:AGTRA

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:AGTRA

involved_in

GO:0001819: positive regulation of cytokine production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:AGTR1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P41495

F

Seeded From UniProt

complete

HUMAN:AGTR1

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:5HT2B

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P25095

F

Seeded From UniProt

complete

RAT:5HT2B

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

SARBU:TMOF

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P30556

F

Seeded From UniProt

complete

HUMAN:5HT2B

involved_in

GO:0001819: positive regulation of cytokine production

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:5HT2B

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:5HT2B

involved_in

GO:0001819: positive regulation of cytokine production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:5HT2B

involved_in

GO:0003300: cardiac muscle hypertrophy

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:5HT2B

involved_in

GO:0050715: positive regulation of cytokine secretion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ANGT

involved_in

GO:0050715: positive regulation of cytokine secretion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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