Heterozygous knockout of neuregulin-1 gene in mice exacerbates doxorubicin-induced heart failure

Fen Fen Liu, James R. Stone, Adam J.T. Schuldt, Katashi Okoshi, Marina P. Okoshi, Masaharu Nakayama, Kalon K.L. Ho, Warren J. Manning, Mark A. Marchionni, Beverly H. Lorell, James P. Morgan, Xinhua Yan

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Abstract

Neuregulins and their erbB receptors are essential for cardiac development and postulated to be cardioprotective in the presence of injury in the postnatal heart. We tested the hypothesis that the development of doxorubicin-induced cardiotoxicity in vivo is more severe in mice with heterozygous knockout of the neuregulin-1 gene (NRG-1+/-) compared with wild-type mice (WT). Three-month old NRG-1+/- and WT mice were injected with a single dose of doxorubicin (20 mg/kg ip). Survival was analyzed by the Kaplan-Meier approach. Left ventricular (LV) function and signaling pathways were analyzed 4 days after treatment. Fifteen days after treatment, survival was significantly lower in doxorubicin-treated NRG-1+/- mice (NRG-1+/--Dox) compared with doxorubicin-treated WT mice (WT-Dox) (15% vs. 33%, P < 0.01). LV mass was significantly lower in NRG-1+/--Dox but not in WT-Dox compared with non treated animals. LV systolic pressure and LV midwall fractional shortening were significantly lower in NRG-1+/--Dox compared with WT-Dox mice. LV protein levels of NRG-1, erbB2, and erbB4 receptors were similar in WT-Dox and NRG-1+/--Dox mice. However, levels of phosphorylated erbB2, Akt, and ERK-1/2 were significantly decreased in NRG-1+/--Dox compared with WT-Dox mice. A significant decrease in phosphorylated P70S6K levels was also observed in NRG-1+/--Dox compared with nontreated NRG-1+/- mice. These results demonstrate that heterozygous knockout of the neuregulin-1 gene worsens survival and LV function in the presence of doxorubicin-induced cardiac injury in vivo. This is associated with the depression of activation of the erbB2 receptor as well as Akt, p70S6K, and ERK-1/2 pathways.

Original languageEnglish
Pages (from-to)H660-H666
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume289
Issue number2 58-2
DOIs
Publication statusPublished - 2005 Aug

Keywords

  • ErbB2
  • Receptors
  • Transgenic mice

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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  • Cite this

    Liu, F. F., Stone, J. R., Schuldt, A. J. T., Okoshi, K., Okoshi, M. P., Nakayama, M., Ho, K. K. L., Manning, W. J., Marchionni, M. A., Lorell, B. H., Morgan, J. P., & Yan, X. (2005). Heterozygous knockout of neuregulin-1 gene in mice exacerbates doxorubicin-induced heart failure. American Journal of Physiology - Heart and Circulatory Physiology, 289(2 58-2), H660-H666. https://doi.org/10.1152/ajpheart.00268.2005