Published online before print August 9, 2004, doi: 10.1161/01.CIR.0000139856.20505.57
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(Circulation. 2004;110:969-974.)
© 2004 American Heart Association, Inc.
Original Articles |
Involvement of the Serotonin 5-HT2B Receptor in Cardiac Hypertrophy Linked to Sympathetic Stimulation
Control of Interleukin-6, Interleukin-1ß, and Tumor Necrosis Factor-
Cytokine Production by Ventricular Fibroblasts
From the Laboratoire de Neurobiologie et de Pharmacologie Cardiovasculaire, INSERM E333, Faculté de médecine, Strasbourg (A.S., L. Monassier); Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, Université L. Pasteur de Strasbourg, Illkirch (F.J., N.E., C.G.N., L. Maroteaux); and Centre de Recherches Claude Bernard, Service de Biochimie, Hôpital Lariboisière, Paris (J.C., J.-M.L.), France.
Correspondence to Laurent Monassier, MD, PhD, Laboratoire de Neurobiologie et de Pharmacologie Cardiovasculaire, INSERM E333, Faculté de médecine, 11 rue Humann, 67085 Strasbourg, France. E-mail laurent.monassier{at}medecine.u-strasbg.fr
Received October 29, 2003; de novo received January 24, 2004; revision received March 16, 2004; accepted March 23, 2004.
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Abstract |
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Background— The serotonergic 5-HT2B receptor regulates cardiomyocyte development and growth. A putative contribution of this receptor to fibroblast-dependent cardiac function has not been identified.
Methods and Results— By mimicking sympathetic stimulation with chronic isoproterenol perfusion in vivo, we found that mice developed a cardiac hypertrophy, which was prevented by exposure to the 5-HT2B receptor antagonists SB206553 or SB215505 or in 5-HT2B receptor–knockout mice. The isoproterenol-induced hypertrophy was associated with an increase in the plasma levels of interleukin-1ß and tumor necrosis factor- but not interleukin-6. In contrast, the plasma isoproterenol-induced cytokine increase was not observed in either 5-HT2B receptor–mutant or wild-type mice perfused with isoproterenol+SB206553. We demonstrated that stimulation of wild-type cardiac fibroblasts by isoproterenol markedly increased the production of the interleukin-6, interleukin-1ß, and tumor necrosis factor- cytokines. Strikingly, we found that this isoproterenol-induced cytokine production was abolished by SB206553 or in 5-HT2B receptor–knockout fibroblasts. Serotonin also stimulated production of the 3 cytokines in wild-type fibroblasts, which was effectively reduced in 5-HT2B receptor–knockout fibroblasts.
Conclusions— Our results demonstrate for the first time that 5-HT2B receptors are essential for isoproterenol-induced cardiac hypertrophy, which involves the regulation of interleukin-6, interleukin-1ß, and tumor necrosis factor- cytokine production by cardiac fibroblasts.
Key Words: fibroblasts • hypertrophy • interleukins • nervous system, sympathetic • remodeling
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Introduction |
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Myocardial hypertrophy has long been considered an adaptive process to increased wall stress in the heart.1 Sustained cardiac hypertrophy is often maladaptive and leads to significant ventricular dysfunction and failure.2 This phenomenon involves not only an increase in size and mass of the cardiomyocytes but equally, the activation of cardiac fibroblasts.3 Recent studies have emphasized the role of G protein–coupled receptors in the initiation of processes that play crucial roles in myocyte hypertrophy4 and fibroblast stimulation.5 Moreover, it was demonstrated that Gq/G11 proteins activated after stimulation of either AT1 angiotensin II (AGII),
1-adrenergic (AR), or ETA endothelin 1 receptors are key regulators of these hypertrophic responses.6 Although the action of these mediators on cardiomyocytes is direct, it also implicates autocrine and paracrine factors. For example, AR stimulation has been demonstrated to induce the release of the hypertrophic cytokines interleukin-6 (IL-6), interleukin-1ß (IL-1ß), and tumor necrosis factor- (TNF-) from cardiac fibroblasts,7 which are the predominant source of cytokines in myocardium.8 In vivo, the 3 cytokines are produced after either myocardial infarction or a cardiac remodeling process9 triggered by sympathetic overstimulation. An increase in serotonin (5-HT) levels has been identified in normal and failing heart,10 and its release could be associated with sympathetic overstimulation,11 contributing to myocardial remodeling in left ventricular dysfunction. The effects of 5-HT are mediated by actions on numerous cognate receptors belonging to the G protein–coupled receptors and ionotropic receptors. Activation of the 5-HT2 Gq/G11-coupled subtypes participates in cell proliferation.12 We have previously shown that 5-HT, via the 5-HT2B receptor (5-HT2BR), regulates cardiac embryonic development and adult functions; gene targeting of the 5-HT2BR gene by homologous recombination leads to a dilated cardiomyopathy without hypertrophy.12,13 Alternatively, the selective overexpression of the 5-HT2BR in cardiomyocytes induces a myocardial hypertrophy,14 and a direct survival effect of 5-HT in cardiomyocytes was placed in evidence.15 Therefore, the Gq-coupled 5-HT2BR could be implicated in trophic responses of the myocardium by acting directly on cardiomyocytes or indirectly on noncardiomyocytes through the release of paracrine factors.
The aims of the present work were to study whether, on ß-adrenergic stimulation, the 5-HT2BR could (1) modify the cardiac hypertrophic responses in vivo and (2) contribute to IL-6, IL-1ß, and TNF- cytokine production by ventricular fibroblasts.
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Methods |
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5-HT2BR–Knockout Mice
Targeted mutagenesis has been described previously.12 Animal experimentation was performed in accordance with institutional guidelines. Protocols were approved by the French Animal Care Committee in accordance with European regulations. 129/PAS (genetic background of KO mice) served as wild-type (WT) controls.
Induction of Cardiac Hypertrophy by Isoproterenol
In 11-week-old mice, vehicle (saline), isoproterenol (ISO) (30 µg · g–1 · d–1) alone, or ISO associated with the 5-HT2BR antagonist SB206553 or SB215505 (1 mg · kg–1 · d–1) (all chemicals from Sigma) was delivered by osmotic minipumps (1007D, Alzet Corporation) implanted subcutaneously under anesthesia (sodium pentobarbital, 40 mg/kg IP). After 5 days, the heart was excised and weighed, and the apex was quickly frozen. The remaining left ventricle was fixed in 4% paraformaldehyde PBS solution. For planimetric quantification of cardiomyocyte area, at least 40 cardiomyocytes were measured on 1 midventricular section. Heart rate was recorded by the tail-cuff method (Letica Model 5002).13 For tele- metric measurements, mice anesthetized with ketamine (100 mg/kg) and xylazine (0.4 mg/kg) were fitted with the TA11PA-C20 sensor model (Data Sciences) placed in the right common carotid artery.16 Seven days later, basal parameters were recorded every 5 minutes over a period of 24 hours before implantation of an osmotic minipump. The mean values of systolic and diastolic blood pressures and heart rate were calculated for the whole of this period. Similarly, the animals were recorded over a period of 24 hours after 7 days of treatment. Transthoracic echocardiograms were performed with a 15-MHz linear transducer on a Sonos 5500 (Philips) in anesthetized mice (sodium pentobarbital, 30 mg/kg IP).13 This anesthetic was selected to exemplify, and reveal, any cardiodepressive property of SB206553 better than echocardiography in the conscious state.
5-HT2R Expression in Fibroblasts
Semiquantitative reverse transcription–polymerase chain reaction was performed on 2 µg of total RNA.13 The following primers were used: 5'-AAGCCTCGAACTGGACAATTGATG-3' (5-HT2AR forward), 5'-AATGATTTTCAGGAAGGCTTTGGTT-3' (5-HT2AR reverse), 5'-ACAACTTCTGAGCACATTTTAAG-3' (5-HT2BR forward), 5'-AATTAACCATACCACTGTAATC-3' (5-HT2BR reverse), 5'-CCCTTATTGACCTCAACTACATGGT-3' (GAPDH forward), and 5'-GAGGGGCCATCCACAGTCTTCTG-3' (GAPDH reverse).
Adult Cardiac Fibroblast Primary Culture
Cultures of fibroblasts were obtained from the ventricles of adult (10- to 12-week-old) mice using a modification of a previously described protocol.17 After anesthesia, the heart was excised and the ventricles, free from the atria and atrioventricular valves, were minced and incubated with 0.1 mg/mL type IV collagenase and 1 mg/mL pancreatin (Sigma) at 37°C. Cells were plated in Dulbecco/Ham F12 medium with 10% calf serum and gentamicin. After a 2-hour incubation period at 37°C in 5% CO2/95% air, the unattached cardiomyocytes were removed, and the attached cells (mostly fibroblasts) were grown. All experiments were performed using cells of the first passage. Cardiac fibroblasts were identified by characteristic morphology and positive staining with antibody to vimentin (Sigma).17 One day before the experiments, cells were transferred to serum-free medium.
Dosage of Cytokines
Cultured fibroblasts corresponding to each time point were plated in 6-well plates. Supernatants and cells were collected at 0, 2, 4, 8, 12, and 24 hours after onset of stimulation. This was performed after stimulation with ISO (10 µmol/L) in the absence or presence of the 5-HT2BR antagonist SB 206553 (100 nmol/L). Cells were stimulated with 5-HT (1 µmol/L) and BW723C86 (BW) (100 nmol/L) (Sigma). The plasma cytokine quantification was performed after centrifugation (2000g, 10 minutes) of 1 mL total blood. Concentrations of IL-6, IL-1ß, and TNF- were measured in plasma and cell culture supernatants by ELISA kits (DY 406, DY 401, and DY 410, R&D).
Binding Assays
Radioligand binding studies of ß1- and ß2-ARs in WT and KO mice hearts were performed according to Molenaar et al.18 ß-ARs were labeled with (–)-[125I]-cyanopindolol (Amersham). The proportions of ß1- and ß2-ARs were determined by use of CGP 20712A (ß1-selective antagonist) and ICI 118,551 (ß2-selective antagonist) (Sigma). Kd and Bmax were obtained from competition curves.
Data Analysis and Statistics
All results are expressed as mean±SEM. Different groups were compared by 1-way ANOVA followed by a Newman-Keuls test. With 2 groups, the comparison was performed using a Student’s t test. All calculations were made with the GraphPad Prism program (San Diego).
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Results |
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Role of 5-HT2BRs in ISO-Mediated Cardiac Hypertrophy In Vivo
We used the classic chronic ß-AR agonist ISO perfusion (30 µg · kg–1 · d–1) as a model of cardiac hypertrophy.19 In WT mice, 5 days of perfusion produced a marked increase in the ratio of cardiac mass to tibia length (CMTL) (59±17%, ISO versus WT) (Figure 1A). The ISO perfusion induced an important tachycardia (62±4% in WT-ISO versus WT) (Figure 1B). The increase in cardiac mass was primarily because of the hypertrophy of cardiomyocytes (Figure 2, A and B). The ISO-induced increase in CMTL was completely prevented by the 5-HT2B/2CR antagonist SB206553 (1 mg · kg–1 · d–1) (Figures 1A and 2
B) but not the ISO-induced tachycardia (Figure 1B). Similarly, the selective 5-HT2BR antagonist SB215505 (1 mg · kg–1 · d–1) prevented the ISO-induced increase in CMTL but not the tachycardia. In 5-HT2BRKO mice, the ISO perfusion produced a slight increase (19%) in CMTL, which was significantly lower than WT ISO-treated mice (Figures 1A and 2B). However, in 5-HT2BRKO mice, ISO induced a tachycardia similar to that observed in WT mice (Figure 1B). The ß1- and ß2-AR expression levels (Bmax) were not significantly different in 5-HT2BRKO mice compared with control animals (Figure 2C); the respective affinity constants (Kd) were also not modified (data not shown). The putative cardiovascular effects of SB206553 (1 mg · kg–1 · d–1) were investigated in WT mice by telemetry and echocardiography. Chronic exposure to this drug modified neither the cardiac function nor the blood pressure in WT mice (Table). The ISO-induced hypertrophy observed in the WT mice is thus dependent on 5-HT2BRs.
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P<0.05 vs WT.
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Role of 5-HT2BRs in ISO-Mediated Increase in Cytokine Plasma Levels
Five days of ISO perfusion in WT mice increased the plasma levels of TNF- significantly (2-fold over basal) and IL-1ß (2-fold) (Figure 3, B and C). These increases were prevented by SB206553. In 5-HT2BRKO, the basal values of these 2 cytokines were not different from those of WT mice, and ISO was unable to increase their plasma concentrations (Figure 3, B and C). In WT mice, the perfusion of ISO, either alone or in combination with SB206553, did not significantly modify IL-6 plasma concentrations, nor did it do so in 5-HT2BRKO. However, basal IL-6 plasma concentration was approximately twice as high in 5-HT2BRKO mice as in WT mice (Figure 3A). Therefore, this ISO increase of TNF- and IL-1ß plasma levels observed in the WT mice was prevented entirely by pharmacological or genetic ablation of 5-HT2BRs.
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Role of 5-HT2BRs on IL-6, IL-1ß, and TNF- Cytokine Production by Cardiac Fibroblasts Stimulated by ISO
We focused on cardiac fibroblasts, the main source of hypertrophic cytokines that are involved in the cardiac remodeling processes.17 Supernatants of primary cultures displayed no difference in basal levels of IL-6, TNF-, and IL-1ß between WT and 5-HT2BRKO. In WT fibroblasts, ISO (10 µmol/L) induced a peak of cytokine production (IL-6, 12-fold over basal; TNF-, 4-fold; and IL-1ß, 2-fold) between 4 and 8 hours of stimulation (Figure 4, A through C). In WT cells treated with SB206553 (100 nmol/L) or in 5-HT2BRKO fibroblasts, a prevention of the ISO-induced production of IL-6, TNF-, and IL-1ß was observed. Therefore, 5-HT2BRs appear necessary for the induction by ISO of the 3 cytokines in cardiac fibroblasts.
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Role of 5-HT2BRs on Cytokine Production by Cardiac Fibroblasts Stimulated by 5-HT
Adult WT cardiac ventricular fibroblasts constitutively express 5-HT2A and 5-HT2BRs (Figure 5A). 5-HT (1 µmol/L) markedly increased IL-6 (6-fold over basal), TNF- (12-fold) and IL-1ß (4-fold) levels in WT fibroblasts at 4 hours after agonist exposure (Figure 5, B through D). In WT fibroblasts, the 5-HT–induced IL-1ß production was mimicked by stimulation with the 5-HT2BR–selective agonist BW (100 nmol/L). BW reproduced 66% of the IL-6 response observed with 5-HT in WT. The response to 5-HT of KO fibroblasts reached only 30% of the WT IL-6 response. For TNF-, BW induced a peak significantly smaller than the response to 5-HT in WT (
50%), although similar to that in 5-HT2BRKO fibroblasts. These findings indicate a role for 5-HT2BRs in the production of these 3 cytokines by cardiac fibroblasts in response to 5-HT.
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P<0.05 vs WT BW. |
Discussion |
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This work demonstrates for the first time that 5-HT2BR blockade in vivo can reduce cardiac hypertrophy caused by ß-AR stimulation. Moreover, 5-HT2BRs are required for the in vivo regulation of TNF-
and IL-1ß cytokine production. Our in vitro results indicate that the 5-HT2BR is a key regulator for IL-6, TNF-, and IL-1ß production by myocardial fibroblasts in response to 5-HT and equally to ß-AR activation, which explains, at least in part, our in vivo findings.
A role for 5-HT2Rs in cardiac hypertrophy linked to hypertension and left ventricular dysfunction was suggested by earlier reports on the antihypertrophic effects of the 5-HT2 antagonist ketanserin.20 More recently, sarpogrelate, a non- selective 5-HT2 receptor antagonist, was reported to reduce the hypertrophic responses in cultured cardiomyocytes, alone or in combination with fibroblasts.21 ß-ARs contribute to the cardiac hypertrophy linked to catecholamine overstimulation22 and to the activation of cardiac fibroblasts in chronic pressure overload.23 Moreover, in rats, the chronic ß-AR stimulation by ISO induces myocardial generation of IL-6, TNF-, and IL-1ß.7 In WT, we demonstrate that the cardiac hypertrophy induced by continuous ISO perfusion is completely prevented by the 5-HT2BR antagonists SB206553 or SB215505 at doses that were previously shown to prevent the BW-induced hyperphagia in freely feeding rats.24 The markedly reduced ISO-induced cardiac hypertrophy in 5-HT2BRKO mice demonstrates the selectivity of the SB compounds. The small residual cardiac hypertrophy to ISO in KO mice could result from unknown compensatory mechanisms to the dilated cardiomyopathy of KO. Such a difference was previously described in angiotensin II 1a receptor–knockout mice (AT1KO) in which the cardiac hypertrophy was not completely prevented after transverse aortic constriction25 or myocardial infarction,26 whereas the AT1 antagonist losartan suppressed entirely the hypertrophic response of WT in the same models.27,28 Furthermore, strong alterations of the AR signaling pathway in 5-HT2BRKO mice are unlikely to explain the reduction of ISO-induced hypertrophic effect, as suggested by the similarities in the number of ß-adrenergic cardiac binding sites and ISO-induced tachycardia in both WT and KO mice.
The ISO-induced increase in TNF- and IL-1ß plasma levels, which is observed in WT, is completely prevented by pharmacological (SB) or genetic ablation of the 5-HT2BR, supporting the in vivo role of this receptor in cardiac IL-6, IL-1ß, and TNF- cytokine production. Similar to rats,7 the increase in plasma IL-6 was not found in response to ISO in either WT or KO mice. The high resting level of plasma IL-6 in KO mice could be of noncardiac origin, because we were unable to detect its mRNA expression in their myocardium (data not shown). Moreover, no inflammatory cells were identified in the myocardium of these animals.13
In ISO-induced cardiac hypertrophy, fibroblasts constitute a main source of hypertrophic cytokines. As expected, we found that ISO increased the production of IL-6, TNF-, and IL-1ß in WT fibroblasts. According to our in vivo results, this increase is prevented by the 5-HT2B/2C antagonist SB206553 at 100 nmol/L,29 which, here, can be considered as a pure 5-HT2BR antagonist, 5-HT2CRs not being expressed either in heart30 or in vasculature.31 Although changes in IL-6 plasma levels could not be detected in vivo, our in vitro results confirm that at least part of the ISO-induced plasma cytokines originate from cardiac fibroblasts.
Our work reveals for the first time that 5-HT markedly increased the production of IL-6, TNF-, and IL-1ß in WT cardiac fibroblasts, which was mimicked by the 5-HT2BR preferential agonist BW. BW exhibits a significantly higher affinity at 5-HT2BR than 5-HT2AR.24 Our work demonstrates that in adult mice cardiac fibroblasts, the 5-HT–induced production of IL-1ß involves only 5-HT2BRs, because the IL-1ß production is eliminated in 5-HT2BRKO fibroblasts, whereas BW provoked a response superimposable to 5-HT in WT cells. The 5-HT2BR is also a main contributor of 5-HT–induced IL-6 and TNF- cytokine production. BW only partially reproduced the maximum 5-HT–induced TNF- or IL-6 responses in WT fibroblasts, with different kinetics for TNF-. In KO cells, these maximum responses are reduced but not eliminated. These findings indicate that stimulation of 5-HT2BRs constitutes an essential trigger for the complete production of TNF- and IL-6 in combination with other 5-HTRs. This result is in agreement with observations indicating that 5-HT stimulates IL-6 production in vascular smooth muscle cells.32 Taken together, these data suggest that 5-HT participates in in vivo cardiac hypertrophy.
The mechanisms by which 5-HT2BRs control ISO-induced IL-6, IL-1ß, and TNF- cytokine production remain to be elucidated. Crosstalk between Gq-coupled 5-HT2BR and Gs-coupled ß-AR signaling pathways could be suggested, because a recent report demonstrated a dual transinhibition of AT1 and ß-AR by an antagonist targeting a single receptor33; the effects of valsartan are obtained in the absence of angiotensin II. These findings support our result showing that the 5-HT2BR antagonist SB206553 blocks the ISO-induced IL-6, IL-1ß, and TNF- cytokine production by cardiac fibroblasts in the absence of 5-HT. The possible existence of complexes formed between ß-ARs and 5-HT2BRs that would explain these interactions is under investigation. Whether hypertrophic responses to agents such as angiotensin II or endothelin 1 could also be affected by 5-HT2B receptor blockade will be examined in subsequent studies.
In conclusion, the lack of a cardiodepressive property of the 5-HT2BR antagonist, together with the essential role of 5-HT2BRs in cardiac hypertrophy triggered by ß-AR stimulation, suggests that 5-HT2BR antagonists could constitute new opportunities to prevent or reduce myocardial remodeling associated with left ventricular dysfunction and sympathetic overactivity.
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Acknowledgments |
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This work has been supported by Centre National de la Recherche Scientifique, Institut National pour la Recherche Médicale, Hôpitaux Universitaires de Strasbourg, and Université Louis Pasteur and by grants from Fondation de France, Fondation pour la Recherche Médicale, Association pour la Recherche Médicale, and the French Ministry of Research, Action Concertée Incitative. F. Jaffré is supported by a fellowship from the Groupe de Réflexion pour la Recherche Cardiovasculaire—Pfizer and Dr Nebigil by the Lefoulon-Delalande Fondation. We thank P. Hickel, L. El Fertak, and A. Guimond for technical assistance and Dr S. Brooks for English corrections.
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