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

研究成果: Article査読

85 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)H660-H666
ジャーナルAmerican Journal of Physiology - Heart and Circulatory Physiology
289
2 58-2
DOI
出版ステータスPublished - 2005 8
外部発表はい

ASJC Scopus subject areas

  • 生理学
  • 循環器および心血管医学
  • 生理学(医学)

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