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(Circulation. 2002;105:1551.)
© 2002 American Heart Association, Inc.

Brief Rapid Communications

Modulation of Anthracycline-Induced Myofibrillar Disarray in Rat Ventricular Myocytes by Neuregulin-1ß and Anti-erbB2

Potential Mechanism for Trastuzumab-Induced Cardiotoxicity

Douglas B. Sawyer, MD, PhD; Christian Zuppinger, PhD; Thomas A. Miller, BA; Hans M. Eppenberger, PhD; Thomas M. Suter, MD

From the Cardiovascular Medicine Section, Department of Medicine, Boston Medical Center and Myocardial Biology Unit, Boston University School of Medicine, Boston, Mass (D.B.S., T.A.M.), and the Institute of Cell Biology, Swiss Federal Institute of Technology, Zurich, and Swiss Cardiovascular Center Bern, Inselspital, Bern, Switzerland (C.Z., H.M.E., T.M.S.).

Correspondence to Thomas M. Suter, MD, Cardiology, Inselspital, CH-3010 Bern, Switzerland. E-mail thomas.m.suter{at}insel.ch

	Abstract

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Background— There is an increased incidence of heart failure in patients treated concurrently with anthracyclines and the chemotherapeutic anti-erbB2 agent trastuzumab (Herceptin). On the basis of our previous studies with recombinant neuregulin-1ß (NRG-1ß), a ligand for the erbB2 receptor tyrosine kinase, we hypothesized that activation of erbB2 by anti-erbB2 versus NRG-1 would cause differential effects on myocyte intracellular signaling as well as anthracycline-induced myofibrillar injury and might potentially account for the clinical toxicity of trastuzumab in the setting of concurrent anthracycline therapy.

Methods and Results— We tested this hypothesis using adult rat ventricular myocytes (ARVMs) in culture, assessing myofibrillar structure by immunostaining for myomesin and filamentous actin. Activation of erbB2, extracellular signal–regulated kinase 1/2 (Erk1/2), and Akt was assessed by use of antibodies to phosphorylated activated receptor or kinase detected by immunoblot. ARVMs treated with doxorubicin (0.1 to 0.5 µmol/L) showed a concentration-dependent increase in myofilament disarray. NRG-1ß (10 ng/mL) activated erbB2, Erk1/2, and Akt in ARVMs and significantly reduced anthracycline-induced disarray. In contrast to NRG-1ß, anti-erbB2 (1 µg/mL) caused rapid phosphorylation of erbB2 but not Erk1/2 or Akt, with downregulation of erbB2 by 24 hours. Concomitant treatment of myocytes with anti-erbB2 and doxorubicin caused a significant increase in myofibrillar disarray versus doxorubicin alone.

Conclusions— NRG-1ß/erbB signaling regulates anthracycline-induced myofilament injury. The increased susceptibility of myofilaments to doxorubicin in the presence of antibody to erbB2 may explain the contractile dysfunction seen in patients receiving concurrent trastuzumab and anthracyclines.

Key Words: erbB2 • cardiotoxicity • neuregulins • anthracyclines • myocytes

	Introduction

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Treatment of metastatic breast cancer with anthracyclines and trastuzumab, a novel therapy derived from an antibody to the erbB2 receptor tyrosine kinase, results in a marked increase of left ventricular dysfunction and symptomatic heart failure.¹ ErbB2 is a member of the epidermal growth factor receptor family, and along with neuregulin and the erbB4 receptor, it plays an essential role in cardiac development.^2–4 We have shown that recombinant neuregulin 1ß (NRG-1ß) activates both erbB2 and erbB4 receptor tyrosine kinase activity and promotes growth, myofilament organization, and survival of isolated cardiac myocytes.^5,6 The clinical observation of the cardiotoxicity of trastuzumab and anthracyclines suggests that the neuregulin/erbB system modulates the response of the myocardium to anthracyclines. Possible mechanisms for this toxicity are alterations in the structure,⁷ gene expression,⁸ and survival⁹ of cardiac myocytes. The main purpose of this study was to test the hypothesis that trastuzumab alters the susceptibility of myocytes to anthracycline-induced myofibrillar disarray. We therefore characterized the effect of anthracyclines on myocyte myofibrillar structure in isolated adult rat cardiac myocytes in primary culture and examined the effect of NRG-1ß and an antibody to erbB2 with properties similar to trastuzumab¹⁰ on erbB2 signaling and anthracycline-induced changes in myofibrillar structure.

	Methods

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Chemicals
Recombinant NRG-1 and NRG-1ß were purchased from NeoMarkers, as were biological-grade antibodies to rodent erbB2 (Clone B10, Ab-9). All other chemicals, including doxorubicin, were purchased from Sigma.

Preparation of Cardiac Myocytes
Adult rat ventricular myocytes (ARVMs) were isolated from female Sprague-Dawley rats weighing 150 to 200 g as previously described.¹¹ Culture medium was based on M-199 (Amimed or Gibco-BRL) and contained 20 mmol/L creatine (Sigma), 1% 100-U/mL penicillin/streptomycin (Gibco-BRL), 10% preselected FCS (Seramed), and 10 µmol/L cytosine arabinoside (Sigma-Aldrich). ARVMs were treated on day 7 in culture.

Immunofluorescence Microscopy
Cell cultures were fixed and myomesin and filamentous actin were stained as previously described with primary antibody to myomesin,¹² secondary antibodies conjugated to FITC or cyanine-5 from Jackson ImmunoResearch, and rhodamine-phalloidin from Molecular Probes. Stained preparations were analyzed with a Leica confocal scanner TCS NT on the inverted microscope Leica DMIRB-E. Myofibrillar disarray was assessed by an investigator blinded to treatment using a Zeiss Axioplan fluorescence microscope equipped with a 63[times] oil immersion objective. A total of 200 to 250 myocytes were counted for each experimental condition in each experiment.

Detection of Erk1/2, Akt/PKB, erbB2, and erbB4 Phosphorylation
Activated Erk1/2 and Akt were detected with a PhosphoPlus Akt/PKB (Ser473) antibody kit and p44/42 MAP kinase assay kit (New England BioLabs Inc) as previously described.¹³ Separate membranes were probed with an anti-Akt/PKB and anti-erk1/2 antibodies to ensure equal loading. Activation of the erbB2 receptor tyrosine kinase was detected as previously described⁵ by immunoprecipitation from volumes of cell lysates in RIPA buffer (500 µg total protein) with antibodies to erbB2 and immunodetection using anti-phosphotyrosine antibody (Santa Cruz Biotechnology), horseradish peroxidase–conjugated goat anti-mouse secondary antibody (Sigma-Aldrich), and chemiluminescence detection.

	Results

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The effect of doxorubicin on myofilament structure was examined in redifferentiated ARVMs at day 7 in culture. Cells were treated with 0.1 or 0.5 µmol/L doxorubicin for 48 hours. Confocal microscopy of doxorubicin-treated myocytes showed the appearance of "moth-eaten," "lattice-like" myofilament structure, with a relative paucity of myomesin staining (Figure 1, a through d). This occurred in the presence of intact chromatin structure, because simultaneous TUNEL staining of myocytes showed no evidence of DNA damage in these myocytes (data not shown). Doxorubicin treatment resulted in a concentration-dependent increase in the number of myocytes with evidence of disarray (Figure 1e). Cells viewed by time-lapse microscopy and subsequent immunofluorescence after fixation showed that myocytes with evidence of myofibrillar disarray continued to beat at the time of fixation (data not shown).

View larger version (72K): [in this window] [in a new window]   Figure 1. Doxorubicin induces myofilament disarray in ARVMs. Confocal images of ARVMs in primary culture stained for filamentous actin (red) and myomesin (green) show typical sarcomeric staining in a control myocyte (a, low power; b, high power) that is disrupted in cells treated with doxorubicin (0.1 µmol/L; c, low power; d, high power). e, ARVMs show dose-dependent increases in the number of myocytes with myofibrillar disarray assessed by actin and myomesin staining pattern. Values are mean±SD, ANOVA overall P<0.0001 followed by a Fisher’s protected least significant difference test, n=8 experiments, 1600 to 2200 cells per experimental criterion.

To test whether erbB2 modulates anthracycline-induced cardiotoxicity, we examined the effect of NRG-1ß and a monoclonal antibody to rat erbB2 on anthracycline-induced myofilament disarray. Like NRG-1ß,⁵ treatment of ARVMs with anti-erbB2 (1 µg/mL) for 10 minutes induced tyrosine phosphorylation of myocyte erbB2, consistent with receptor activation (Figure 2a). After 24 hours of exposure to the antibody, readdition of antibody caused no further activation of erbB2, consistent with downregulation of erbB2 by this antibody.¹⁰ Activation of erbB2 by anti-erbB2 had no effect on activation of Erk1/2 or Akt, in contrast to NRG-1ß, which activates both kinases⁶ (Figure 2b). Treatment of ARVMs simultaneously with NRG-1ß (50 ng/mL) and doxorubicin decreased the number of myocytes showing evidence of disarray (Figure 2c). There was no significant effect of NRG-1 on baseline or doxorubicin-induced disarray (data not shown). In contrast, treatment with anti-erbB2 and doxorubicin increased the number of myocytes showing a pattern of disarray (Figure 2d). Neither NRG-1ß nor anti-erbB2 alone had any effect on myofibrillar disarray under control conditions (data not shown).

View larger version (31K): [in this window] [in a new window]   Figure 2. NRG-1ß and anti-erbB2 activation of erbB2, intracellular signaling, and effect on anthracycline-induced disarray. a, NRG-1ß and anti-erbB2 activate erbB2 phosphorylation to a similar extent (4.8±1.2-fold of control for anti-erbB2, n=5, vs 4.2-fold of control for NRG-1ß, n=2). Twenty-four-hour treatment with anti-erbB2 reduced the level of receptor phosphorylation to baseline, and there is no further activation of receptor with restimulation. Blot is representative of 4 separate experiments. b, As we have previously reported,6 NRG-1ß caused 2-fold increase in phospho-Erk in ARVMs. In addition, NRG-1ß activated phosphorylation of Akt (2.6±0.8-fold of control, n=3). There was no activation of either Erk1/2 or Akt by anti-erbB2 (0.9±0.1-fold of control for Erk, 1.2±0.3-fold of control for Akt, n=5). c, d, NRG-1ß attenuated doxorubicin-induced myofibrillar disarray, whereas anti-erbB2 increased doxorubicin-induced myofibrillar disorganization. Values are mean±SD, 2-way ANOVA, P=0.007 for anti-erbB2, P=0.025 for NRG-1ß effect on doxorubicin-induced disarray, n=8 experiments, 1600 to 2200 cells per experimental criterion.

	Discussion

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The erbB2 receptor tyrosine kinase is expressed in the myocardium by ventricular myocytes and is essential for normal cardiac development.² Activation of erbB2 and erbB4 by recombinant NRG-1ß leads to myocyte growth and inhibition of apoptosis in vitro.⁵ The present findings support a role for the NRG/erbB system in modulating myocardial response to anthracycline-induced injury. Moreover, these observations suggest a potential mechanism for the clinical observation of increased cardiotoxicity of anthracyclines in patients receiving trastuzumab, a monoclonal antibody to erbB2.¹

Anthracycline-induced myocardial injury is accompanied by an increase in myofibrillar disarray that is seen in patients,¹⁴ animals treated with anthracyclines in vivo,¹⁵ and in vitro studies of cardiac myocytes.⁷ The close relationship between myocyte ultrastructural damage and contractile dysfunction after anthracycline therapy suggests a mechanistic relationship.¹⁶ We found that even myocytes with evidence of myofibrillar degradation continue to beat in culture, although presumably these damaged cells generate less force. That these cells are viable, without evidence of DNA fragmentation, suggests that this damage may be reversible. It is also interesting that myofibrillar damage after anthracycline treatment both in vivo¹⁴ and in vitro (our own data, as well as Reference ⁷) is patchy, with affected myocytes seen adjacent to structurally normal myocytes. This suggests that the effect of anthracyclines on myofibrillar structure is at least in part controlled locally.

The NRG/erbB system may be one form of local control. NRG-1ß is expressed in microvascular endothelial cells and acts on the erbB2 and erbB4 receptors to alter myofilament structure in isolated myocytes via a phosphatidyl inositol (PI) 3 kinase–dependent pathway.⁶ Although both anti-erbB2 and NRG-1ß induced similar degrees of phosphorylation of the erbB2 receptor in the short term, they had opposite effects on doxorubicin-induced changes in myofilament structure. The distinct intracellular signaling induced by NRG-1ß versus the anti-erbB2 is consistent with a role of Erk1/2 and/or Akt in mediating protection of myocytes against anthracycline-induced myofilament disarray. The deleterious effect of anti-erbB2, conversely, might occur through downregulation of erbB2 expression, suppression of intracellular signaling, or other mechanisms.

It is important to note that most women receiving trastuzumab without concurrent anthracyclines did not develop left ventricular dysfunction or overt heart failure.¹⁷ This suggests heterogeneity in the baseline activity of the NRG/erbB system among individuals, resulting from either genetic predisposition or, more likely, environmental stress. Our own data in vitro with anti-erbB2 support the latter conclusion, because we saw a deleterious effect of anti-erbB2 only in the presence of anthracyclines, arguably a source of "stress." The variability in the clinical toxicity of trastuzumab may thus be a result of various degrees of superimposed hemodynamic or other stress during trastuzumab therapy. Carefully monitored use of trastuzumab in cancer victims with other cardiovascular conditions, including aortic stenosis, hypertension, and ischemic heart disease, will help to address this hypothesis.

	Acknowledgments

 
This work was supported in part by National Institutes of Health grant HL-03878 to Dr Sawyer, Swiss National Science Foundation (SNF) grants 3231-054985.98/1 (SCORE A) and 32-55136.98 and a grant from the Swiss Heart Foundation to Dr Suter, SNF Swiss Priority Program 5002-046083 to Dr Eppenberger, and a grant from Genentech to Dr Sawyer. We thank Enzo Buscetti for technical assistance and Monika Eppenberger-Eberhardt and Jean-Claude Perriard for helpful discussions.

Received November 29, 2001; revision received February 5, 2002; accepted February 5, 2002.

	References

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This Article Abstract Full Text (PDF) All Versions of this Article: 105/13/1551    most recent 01.CIR.0000013839.41224.1Cv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sawyer, D. B. Articles by Suter, T. M. Search for Related Content PubMed PubMed Citation Articles by Sawyer, D. B. Articles by Suter, T. M. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB DOXORUBICIN Related Collections Cell biology/structural biology Cell signalling/signal transduction Growth factors/cytokines Heart failure - basic studies