Modulation of anthracycline-induced myofibrillar disarray in rat ventricular myocytes by neuregulin-1β and anti-erbB2: Potential mechanism for trastuzumab-induced cardiotoxicity

• Published in: Circulation (New York, N.Y.) Vol. 105; no. 13; pp. 1551 - 1554
• Main Authors: SAWYER, Douglas B, ZUPPINGER, Christian, MILLER, Thomas A, EPPENBERGER, Hans M, SUTER, Thomas M
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 02.04.2002
• Subjects: Biological and medical sciences; Drug toxicity and drugs side effects treatment; Medical sciences; Pharmacology. Drug treatments; Toxicity: cardiovascular system; Antineoplastic agent; Heart; Heart failure; Rat; Toxicity; Rodentia; Cardiovascular disease; Biological activity; Myocyte; Vertebrata; Mammalia; Heart disease; Animal; Arthropathy; Neuregulin; Anthracyclins
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.0000013839.41224.1C

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-1β (NRG-1β), 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-1β (10 ng/mL) activated erbB2, Erk1/2, and Akt in ARVMs and significantly reduced anthracycline-induced disarray. In contrast to NRG-1β, 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-1β/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.