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Human cardiomyocyte hypertrophy induced in vitro by gp130 stimulation

Cecile Ancey , Emmanuelle Menet , Pierre Corbi , Sandra Fredj , Martine Garcia , Catherine Rücker-Martin , Jocelyn Bescond , Franck Morel , John Wijdenes , Jean-Claude Lecron , Daniel Potreau
DOI: http://dx.doi.org/10.1016/S0008-6363(03)00346-8 78-85 First published online: 1 July 2003

Abstract

Objectives: Recent in vivo and in vitro studies in animals have demonstrated that cytokines of the IL-6 family are involved in cardiac hypertrophy and in protection of cardiomyocytes against apoptosis. The present study aims to analyse the capacity of human atrial cardiac cells (i.e., cardiomyocytes and fibroblasts) to display the gp130 receptor subunit, and to evaluate its functionality. Methods: Twenty human atrial biopsies were used for immunohistochemistry, in situ hybridisation, and western blot analysis or dissociated for isolation and primary culture of cardiac cells. Results: Fibroblasts present in tissue or maintained in primary culture clearly express gp130 whereas the signal in cardiomyocytes is weaker. Culture of cardiac cells with a gp130 agonist antibody enhances atrial natriuretic peptide (ANP), β myosin heavy chain (β-MHC) expression in cardiomyocytes, and significantly increases the cell surface area (μm2). This process could involve STAT3 (signal transducer and activator of transcription 3) phosphorylation. Conclusions: These results demonstrate that gp130 activation in human cardiac cells leads to cardiomyocyte hypertrophy. We discuss several hypotheses on the role of IL-6-type cytokines on cardiomyocyte functions.

Keywords
  • Cardiomyocytes
  • gp130
  • Human heart
  • Hypertrophy
  • Interleukin-6

Time for primary review 29 days.

1 Introduction

Interleukin-6 (IL-6) and its family composed of IL-11, leukaemia inhibitory factor (LIF), cardiotrophin-1 (CT-1), oncostatin M, ciliary neurotrophic factor and CLC–CLF (the heterodimeric complex of cardiotrophin-like cytokine and the soluble receptor cytokine-like factor 1), are cytokines sharing pleiotropic actions [1–4]. IL-6 exerts its function through a cell surface receptor composed of two transmembrane proteins belonging to the class I cytokine receptor family, an 80-kDa ligand-binding subunit designated as IL-6 receptor (IL-6R) and a signal transducing 130-kDa glycoprotein (gp130) [5]. Binding of IL-6 to IL-6R triggers the association of IL-6R and gp130 and the homodimerization of gp130, which leads to activation of the Janus kinase-STAT (Signal transducer and activator of transcription) activation pathway. gp130 is also involved in the signalling pathway of the other cytokine members of the IL-6 family [2,4] which explains the overlapping properties of these cytokines. However, the nature of the gp130–cytokine/receptor interactions and the selective usage of members of the Janus kinase-STAT families, in addition to the multiple signal-transduction pathways induced by a cytokine are able to orchestrate a specific response ([6,7] for reviews)

Numerous studies have shown that cytokines of the IL-6 family induce cardiomyocyte hypertrophy and inhibit their apoptosis. In 1995, Pennica et al. [8] demonstrated that CT-1 induces cellular hypertrophy in ventricular new-born rat cardiomyocytes in culture. Independently, Hirota et al. [9] showed that continuous activation of gp130 in a transgenic model (overexpressing IL-6 and IL-6R) induced postnatal cardiac hypertrophy. Conversely, constitutive gp130 inactivation induces embryonic lethality associated with hypoplastic development of the hearts of embryos [10], and gp130 postnatal inactivation induces heart atrophy [11]. Those results strongly suggest that gp130 is involved in heart development by regulating hyperplasia before birth and inducing hypertrophy after birth. Adult mice with a cardiac restricted gp130 knockout present a rapid onset of dilated cardiomyopathy and a massive induction of myocyte apoptosis during aortic pressure overload, whereas control mice display compensatory hypertrophy [12]. This suggests that in myocardial disorders, the cytokines of the IL-6 family may prevent heart failure by inducing compensatory hypertrophy thus inhibiting apoptosis of cardiomyocytes [13]. Hypertrophy induction is mainly triggered through a STAT3 pathway whereas anti-apoptotic activity is triggered through a mitogen activated protein kinase pathway [14].

During congestive heart failure [15,16] or systemic sclerosis [17], high IL-6 plasma levels have been measured. IL-6 mRNA has been detected after ischemia-reperfusion in the myocardium of swine or dogs [18,19]. When adult rats are submitted to an experimental infarct, it has been shown that non-myocytes, which constitute up to 70% of the ventricular myocardial cells, express inflammatory cytokines (IL-6, IL-1β and tumor necrosis factor α) that are involved in extracellular matrix changes during heart remodelling [20].

We have recently shown that human cardiomyocytes are able in vitro to produce LIF, whereas both cardiac fibroblasts and cardiomyocytes produce IL-11 and very high levels of IL-6 [21]. We have also reported that human pericardium is a potent IL-6 producer [22]. Moreover, there is a huge increase of IL-6 plasma concentration during cardiopulmonary surgeries, mainly linked to surgical trauma rather than to extracorporeal circulation bypass [23]. Interestingly, it has been shown recently that both IL-6 and gp130 mRNA and proteins were significantly increased in the myocardium of patients with advanced heart failure in comparison with a control group [24]. Zolk et al. [25] also reported an enhancement of gp130 mRNA in failing human hearts, but a diminution of the gp130 protein.

The aim of this study was to analyse gp130 expression in adult human atrial myocardium using histological methods on atrial tissue slices and isolated cells. STAT3 phosphorylation, atrial natriuretic peptide (ANP), β myosin heavy chain (β-MHC) expression and cardiomyocyte size were studied in order to explore the functionality of the gp130 activation pathway. We demonstrate that in vitro activation of the gp130 pathway in human atrial cells leads to hypertrophy of cardiomyocytes.

2 Methods

2.1 Patients

Twenty patients (61±10 years) were enrolled for the study between April 1999 and May 2002. They were operated on for coronary artery disease in the cardio-thoracic surgery units (Poitiers Hospital, France and Marie Lannelongue Hospital, Le Plessis Robinson, France). Patients with preoperative inflammatory disease, previous cardiac surgery, left ventricle impairment, atrial fibrillation or referred in emergency were excluded. Enrolled patients were prepared for surgery in a similar way. Atrial myocardium specimens of the right appendage (about 1–2 g) were necessarily removed in order to canulate for cardiopulmonary bypass with extracorporeal circulation. The use of these samples for research studies was approved by the Ethics Committees of Poitiers and Marie Lannelongue Hospitals. Among the 20 biopsies used, 5 were fixed for immunostaining and in situ hybridisation, 10 were dissociated for cultures, and 5 were used for Western blot experiments.

2.2 Cardiomyocyte dissociation and cell culture

Cardiac cells, comprised of both fibroblasts and cardiomyocytes, were dissociated as previously described [21,26]. Briefly, biopsies of human cardiomyocytes were cut in small pieces and washed in solution A (10 mM Hepes, 35 mM NaCl, 10 mM glucose, 134 mM sucrose, 16 mM Na2HPO4, 25 mM NaHCO3, 7.75 mM KCl, 1.18 mM KH2PO4, pH 7.4) supplemented with 30 mM 2,3-butanedione 2-monoxime and 0.5 mM EGTA. The first digestion step was performed in solution A supplemented with 0.5% BSA (bovine serum albumin), 200 UI/ml of collagenase type V and 6 UI/ml protease type XXIV (Sigma, MO, USA) for 20 min followed by four digestion steps with 400 UI/ml collagenase type V. All steps were carried out at 37°C, in the presence of 95% O2 and 5% CO2. Dissociated cells were gently centrifuged (30 g, 1 min, room temperature) to concentrate cardiomyocytes in the pellet. This enriched fraction of cardiomyocytes contains residual fibroblasts. These cells were seeded at a density of 50,000 cells/ml on a 20-μg/ml laminin (Sigma) pre-treated support and cultivated in DMEM supplemented with 10% foetal calf serum, 2% of non-essential amino acids, 1 U/ml Na-Penicillin G, 0.5 U/ml streptomycin (GIBCO-BRL, Paisley, Scotland) and 10−9 M insulin (Sigma). In some experiments, cultures were performed with 10 μg/ml cytosine β-d-arabinofuranoside (Ara C) in order to inhibit fibroblast proliferation. Fibroblasts enriched populations present in the first step centrifugation supernatant were obtained by an additional faster centrifugation (150 g, 5 min, room temperature) and cultured on non-treated supports in the same medium as cardiomyocytes. Fibroblast identification was performed by fibronectin immunolabeling (data not shown). Cells were incubated at 37°C in a humidified, 5% CO2-enriched atmosphere. These cells were cultured for a period of 8 days and culture medium was completely changed every 2 days. To test effects of gp130 stimulation on cardiomyocyte hypertrophy, a gp130 agonist monoclonal antibody (mAb), B-S12 (Diaclone, Besançon, France) was added to cultures at a concentration of 50 μg/ml. To block its activation, a gp130 antagonist mAb B-R3 (Diaclone) and an anti-IL-6 mAb B-E8 (Diaclone) were added in to cultures at a concentration of 50 μg/ml [27].

2.3 In situ hybridisation

In situ hybridisation was performed on myocardium tissue fixed for 24 h with 10% paraformaldehyde. We used digoxigenin-labelled probes (8 μg/ml) prepared by PCR methodology. A vector containing human gp130 cDNA was used as a template. We used specific primers (Eurogentec, Herstal, Belgium): 5′ TTT CCA TTG GCT TCA AAA GG 3′ and 5′ TGC TGA TTG CAA AGC AAA AC 3′ amplifying a 579-bp sequence. PCR reactions were performed with 400 μM of dNTP labeling mix (DIG DNA labeling kit (Boehringer Mannheim, Meylan, France), 2 mM of MgCl2 (Perkin Elmer, Shelton, CT, USA), 0.5 μM of each primer, 60 U/ml of Taq polymerase (Perkin Elmer) and 100 pg of plasmid DNA extracted with Wizard plus SV minipreps kit (Promega, Madison, WI, USA). Reactions were initiated by heating at 94°C for 10 min, then 40 cycles were performed with denaturation at 94°C for 45 s, annealing at 52°C for 45 s and extension at 72°C for 45 s. A final step of 10 min at 72°C was performed. The relevance of PCR products was verified by sequencing with an automated fluorescence-based system (ABI Prism 310, Applied Biosystems, Foster City, CA, USA) using the ABI Prism BigDye Terminator cycle sequencing kit (Applied Biosystems). In situ hybridisation was performed as previously described by Choi et al. [28] using the DIG DNA labeling kit (Boehringer Mannheim).

2.4 Immunohistochemistry

Immunohistochemistry was performed on biopsies immediately frozen in liquid nitrogen after removal from patients. Serial 15 μm-thick sections were cut with a cryostat at −20°C, collected on slides and stored at −20°C until use. They were stained for immunohistochemistry using the indirect immuno-alkaline phosphatase method. Briefly, slices were treated for 10 min with 4% paraformaldehyde at room temperature and washed three times with phosphate-buffered saline (PBS). Samples were permeabilised for 10 min with 0.5% Triton X100-PBS and washed three times with PBS. An anti-human gp130 mAb (B-R3, Diaclone) was used as the primary antibody in 1% BSA–0.1% saponin-PBS. This mAb was detected with alkaline phosphatase-conjugated rabbit anti-mouse IgG (Jackson Immunoresearch Laboratory, West Grove, PA, USA). Fast-red (Sigma) was used as a chromogen and slides were counterstained with hemalun. The specificity of the mAb was confirmed by the absence of a signal in serial sections when the primary antibody was omitted or replaced by an irrelevant antibody of the same isotype.

2.5 Immunostaining of cultured cells

Cultured cells were stained by an indirect immunofluorescence method as described above for immunohistochemistry. B-R3, an anti-human gp130 mAb (Diaclone), an anti-ANP rabbit polyclonal antibody (AA 1105; Santa Cruz Biotechnology, Santa Cruz, CA, USA) and an anti-β-MHC mAb (Biocytex Biotechnology, Marseille, France) were used in 1% BSA-PBS. MAbs were detected with CY2-conjugated goat anti-mouse IgG (Jackson Immunoresearch Laboratory) and polyclonal antibodies were detected with CY3-conjugated goat anti-rabbit IgG (Jackson Immunoresearch Laboratory). The fluorescent markers CY3 and CY2 were respectively excited at 568 and 488 nm with the krypton/argon laser beam of a confocal microscope system (MRC 1024; Bio-Rad, Hemel Hemstead, UK), with the emission signal collected respectively via a 585- and a 522-nm long pass filter. Fluorescence signal collection, image construction, cell surface measurement and scaling were performed through the control software (Laser-Sharp; Bio-Rad). The Laser-Sharp program is able to calculate surface area of polygons in μm2. Cell outlines as polygons were then drawn on confocal sections passing through the nucleus, leading to the cell surface area automatic calculation.

2.6 Western blot analysis of the phosphorylation of STAT3

Human atrial biopsies were cut in small pieces in NaCl 0.9% and incubated at 37°C for 0, 1, 2, 5 and 10 min, in culture medium alone or supplemented by B-R3 mAb 50 μg/ml plus B-E8 mAb 50 μg/ml to inhibit gp130 pathway. Thereafter, sample lysis was performed at 4°C in a buffer containing 50 mM Tris, 150 mM NaCl, 1% Nonidet P-40, 50 mM Na3VO4, 1 mM NaF, 1 mM phenylmethylsulfonyl fluoride, and 1 μg/ml anti-proteases. Sixty micrograms of protein were diluted in sample buffer (100 mM Tris HCl pH 6.8, 2% sodium dodecylsulfate, 5% β-mercaptoethanol, 2.5% glycerol and 0.1% bromophenol blue) and boiled for 5 min. Samples were resolved on a 10% sodium dodecylsulfate–polyacrylamide gel and then transferred to nitrocellulose membranes (Amersham, Arlington Heights, IL, USA) using a liquid blot system. Blots were blocked at room temperature in Tris bufferred saline (TBS) pH 7.4 supplemented with 5% bovine serum albumin (BSA) for 2 h. The anti-phospho-STAT3 polyclonal antibody (New England Biolabs, Hertfordshire, UK) was incubated overnight at 4°C in TBS 5% BSA. After washing, blots were incubated for 1 h at room temperature with peroxidase-labelled goat anti-rabbit IgG (1:5000; Kirkegaard & Perry laboratories, Gaithersburg, MD, USA). Detection of labelled proteins was performed using chemiluminescence (ECL detection reagents, Amersham) according to the manufacturer's instructions. Thereafter, blots were stripped in 0.1 M glycine pH 2.7 at room temperature for 2 h. Blots were blocked for 2 h at room temperature in 5% non-fat lyophilised milk TBS, and anti-STAT3 polyclonal antibody was added (Santa Cruz Biotechnology) overnight at 4°C. Detection was performed as described above.

2.7 Statistical analysis

Data were expressed as mean values±standard errors of the mean. Differences between groups were analysed by one-way analysis of variance (ANOVA) followed by the Newman–Keuls post test. A P-value <.05 was considered statistically significant.

3 Results

3.1 gp130 expression in adult human myocardium

gp130 receptor subunit expression was analysed on human atrial tissue slices by immunolabeling and in situ hybridisation. gp130 protein (Fig. 1B) and mRNA (Fig. 1C) were observed in fibroblasts, characterised as spindle-shaped cells surrounded with collagen while the signal for the gp130 protein is clearly weaker in cardiomyocytes, organised in rows. Panel A shows the immunohistochemical labeling observed in the presence of an irrelevant primary mAb as a negative control. Phenotypic analysis of cultured isolated cardiac cells confirmed the presence of high levels of gp130 receptor subunits on fibroblasts, as shown by confocal section (Fig. 1D). Whereas about all the fibroblasts strongly expressed gp130, its very low level on cardiomyocytes did not allow a reliable quantification.

Fig. 1

gp130 expression in cardiac cells. Immunostaining was performed on 15 μm-thick frozen transversal sections with the B-R3 anti-gp130 mAb (B), or with an irrelevant mAb as a control (A), detected with an alkaline phosphatase-conjugated secondary antibody and fast-red as a chromogen. Nuclei were counterstained with hemalun. In situ hybridisation was performed on 4 μm-thick paraffin embedded sections using digoxigenin-labelled gp130 probes (C). Open arrows indicate positive cells. Fluorescent immunostaining on 4 day-cultured fibroblasts was performed with the B-R3 anti-gp130 mAb detected with a CY2-conjugated second antibody (a confocal section, panel D). Scale bars correspond to 10 μm.

3.2 STAT3 phosphorylation in human atrial tissue after gp130 stimulation

STAT3 phosphorylation through gp130 activation was assessed by western blot technique performed on human atrial biopsies. Phosphorylation of STAT3 was revealed by using a specific phospho-STAT3 antibody, which was compared to the total levels of STAT3, revealed by an anti-STAT3 antibody (Fig. 2). Kinetic studies demonstrated that the STAT3 phosphorylation was detectable as soon as 1 min, reaching a plateau at 2 min when the samples were incubated in culture medium alone at 37°C (Fig. 2A). In the presence of a combination of IL-6 (B-E8) and gp130 (B-R3) blocking mAbs for 10 min, STAT3 was not phosphorylated, in contrast to tissue incubated 10 min in culture medium alone (Fig. 2B).

Fig. 2

Western blot analysis of phospho-STAT3 (P-STAT3) and total STAT3 (tSTAT3) in adult human atrial myocardium extracts. (A) Kinetic analysis of STAT3 phosphorylation in control medium. Samples were lysed (T0), or incubated 1, 2, 5 and 10 min before lysis. (B) The combination of gp130 and IL-6 blocking mAbs inhibits STAT3 phosphorylation after 10 min of incubation (I), when compared to samples incubated in medium alone (C). This experiment is representative of five similar independent experiments.

3.3 Cardiomyocyte hypertrophy induced by gp130 stimulation

To investigate the effects of gp130 activation on adult human cardiomyocyte hypertrophy, we cultured atrial cells in primary cultures, containing both cardiomyocytes and fibroblasts, in the presence of gp130 agonists or antagonists. In addition to the measurement of the cardiomyocyte surface area, the expression of ANP and β-MHC, two well-known parametrical indexes of cardiac hypertrophy, were analysed by immunostaining on 8 day-cultured cardiac cells. ANP expression (red) was clearly observed in myocytes grown under control conditions (Fig. 3A) or in the presence of gp130 agonist, B-S12 (Fig. 3B), while a lower signal was observed in the presence of gp130 and IL-6 blocking mAbs, B-R3 and B-E8 (Fig. 3C). In cells treated with gp130 agonist, β-MHC (green) was much more organised in striated filaments, and cardiomyocytes were significantly larger (13680±1458 μm2, n = 15) than those grown in control medium (8747±612 μm2, n = 15) or in the presence of antagonists (8322±1298 μm2, n = 12) (Fig. 4). In the presence of Ara C, inhibiting fibroblast proliferation, cardiomyocytes grown with gp130 agonist were also larger (11140±1201 μm2, n = 16) than those grown in medium alone (7663±687 μm2, n = 12) or with gp130 and IL-6 blocking mAbs (6661±921 μm2, n = 11).

Fig. 4

Cardiomyocyte surface area measured after 8 days of culture in the presence of proliferating fibroblasts (−Ara C) or not (+Ara C), with or without gp130 agonist (B-S12) or gp130 and IL-6 blocking mAbs (B-R3 and B-E8). Data are expressed as mean±S.E.M. Horizontal bars indicate statistics: ns: non significant; *: P<0.05; **: P<0.01. Similar results were obtained from two other independent experiments.

Fig. 3

Immunostaining of β-MHC and ANP on 8 day-cultured cardiac cells. Cells were seeded in culture medium alone (A), in the presence of gp130 agonist, B-S12 (B), or in the presence of gp130 antagonist, B-R3 and an anti-IL-6 mAb, B-E8 (C). The anti-β-MHC mAb was detected with a CY2-conjugated second antibody, and the anti-ANP polyclonal antibody with a CY3-conjugated second antibody. Images were obtained from a confocal microscope. Scale bars correspond to 10 μm.

4 Discussion

Our results show that the activation of the gp130 pathway induces hypertrophy of human cardiomyocytes in culture. We have detected gp130 receptor subunit mRNA and protein in fibroblasts, and a clearly weaker signal on cardiomyocytes. According to these results, Plenz et al. recently reported that gp130 is preferentially found on interstitial cells of the human heart rather than on cardiomyocytes, and that only a few of them are stained weakly [24]. In addition, these authors show that gp130 mRNA expression is weaker in the right atrium than in other chamber walls. In agreement with these data, we have not been able to perform a reliable quantification on the frequency of gp130-positive right atrial cardiomyocytes studied herein. We hypothesize that the low gp130 expression detected in adult cardiomyocytes could be the consequence of its modulation. Supporting this point, a low level of gp130 has been reported in adult rat cardiomyocytes, increasing after ischemia reperfusion [29] or myocardial infarction [30]. We also performed gp130 immunolabeling on rat heart at different ages and observed the presence of a weak signal on normal cardiomyocytes from adults, whereas the signal is strongest on cardiomyocytes from neonates and on hypertrophied cardiomyocytes of adult hypertensive rats (Unpublished data). Two independent groups reported an upregulation of gp130 mRNA levels in end-stage heart failure [24,25]. Nevertheless, Zolk et al. showed a decrease of the gp130 protein [25]. They suggest that gp130 receptor downregulation balances enhanced CT-1 expression in human heart failure and thereby prevents an excessive activation of the gp130 signalling pathway.

We observed a spontaneous phosphorylation of STAT3 after short term incubation of cardiac cells in culture medium, which was inhibited by the presence of gp130 and IL-6 blocking mAbs. These experiments clearly demonstrate that a functional gp130 pathway is present in human myocardium, leading to STAT3 activation and cardiac hypertrophy, as previously described [14,25]. Such a direct action of the IL-6-type cytokines was previously reported in studies of cardiac myocyte growth [14], as well as on cardiac myocytes hypertrophy [8,9]. It has also been shown that the angiotensin II-induced hypertrophy in newborn rat cardiomyocytes could be mediated by cytokines of the IL-6 family secreted by fibroblasts [31,32]. We previously reported that human cardiac cells in cultures were able to spontaneously produce IL-6, IL-11 and LIF [21]. This suggests that STAT3 phosphorylation observed in short term cultures could be the consequence of an autocrine activation of gp130. IL-6 synthesis by cardiomyocytes was previously reported in animals submitted to surgical stress such as cardiopulmonary bypass [33] or in pathological conditions like ischemia [19]. Other studies have demonstrated that CT-1 can also be synthesised by cardiomyocytes [34] and overexpressed in human failing hearts [25,35]. In our experiments, samples were removed for cardiopulmonary bypass during cardiac surgery. Under these conditions, numerous studies have reported elevated IL-6 concentrations in sera, mainly due to the stress of surgery rather than to the extracorporeal circulation [23]. The presence of high levels of IL-6 mRNA in samples of human explanted normal hearts in comparison to the absence of detectable levels in control biopsies strengthen this hypothesis [24]. We suggest that the stress inherent to our surgical working conditions is close to the stress induced by the sampling of explanted hearts of brain-dead patients, in comparison to direct biopsies of right ventricular myocardium of non-failing patients with arrhythmias. In our conditions, we mimic an acute inflammatory state, as revealed by the spontaneous phosphorylation of STAT3 shown in vitro, suggesting such an activation in vivo during inflammatory diseases or in peri-operative periods.

Our previous study demonstrated that cardiomyocytes and fibroblasts are both high IL-6 producers [21]. IL-6 synthesized by cardiac cells has several potent roles on the heart. It has been shown in vitro [8] and in vivo on animals [9,13], that the cytokines of the IL-6 family induce hypertrophy of ventricular cells. These factors also protect cardiomyocytes from apoptosis [12]. Studies of gp130 knockout mice confirmed that IL-6-type cytokines play a critical role in heart development [10] and on muscle cell survival in the onset of heart failure during biochemical and physical stress [12].

Since human fibroblasts are able, like cardiomyocytes, to produce IL-6, a role for fibroblasts in the autocrine/paracrine effect of these cytokines on heart can be also considered. Our results clearly show that human adult cardiomyocytes are able to respond to gp130 stimulation, even in the absence of proliferating fibroblasts. As previously suggested [36], we thus propose that IL-6 is able to stimulate cardiomyocytes via a paracrine pathway involving fibroblasts. Under those conditions, IL-6 would act on fibroblasts, which would secrete a paracrine factor able to further induce cardiomyocyte hypertrophy. Such a hypothesis is attractive in the context of the increasing potential role given to fibroblasts in the differentiation–dedifferentiation processes of cardiomyocytes [37,38], but remains to be demonstrated.

Taken together, our results demonstrate that despite low levels of gp130 on cardiomyocytes, the activation of the gp130 pathway in human adult atrial cells leads to cardiomyocyte hypertrophy. Since high levels of IL-6 can be produced in the heart, we hypothesize an autocrine and/or a paracrine effect in which fibroblasts could be involved. We suggest that the action of the IL-6 family of cytokines on cardiac functions could be modulated during cardiac surgery and acute inflammation.

Acknowledgements

This study was supported by grants from a clinical research program from Poitiers University Hospital, from the ‘Association Française contre les Myopathies’ and from ‘La Région Poitou-Charentes’. The authors wish to thank Anne Cantereau, Francoise Mazin, Chantal Jougla and Adriana Delwail for expert technical assistance, Drs Mohammad Rahmati, Loic Macé and Patrice Dervanian for their contribution in biopsy collection and Dr Bruce Koppelman for his careful review of the manuscript.

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View Abstract