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1 Cardiovascular Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
2 Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
3 NRG Biotech, Arlington, MA, USA
* To whom correspondence should be addressed. E-mail: xyan{at}bidmc.harvard.edu.
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 knock out 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, i.p.). Survival was analyzed by the Kaplan-Meier approach. Left ventricular (LV) function and signaling pathways were analyzed four days after treatment. Fifteen days after treatment, survival was significantly lower in doxorubicin-treated NRG-1+/- (NRG-1+/--Dox) compared with doxorubicin-treated wild type 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. LV protein levels of NRG-1, erbB2 and erbB4 receptors were similar in WT-Dox and NRG-1+/--Dox. However, levels of phosphorylated erbB2, Akt and ERK1/2 were significantly decreased in NRG-1+/--Dox compared with WT-Dox. A significant decrease in phosphorylated P70S6K levels was also observed in NRG-1+/--Dox compared with non-treated NRG-1+/-. These results demonstrate that heterozygous knock out 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 ERK1/2 pathways.
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