The Effects of Neuropeptide Y Overexpression on the Mouse Model of Doxorubicin-Induced Cardiotoxicity

Doxorubicin is a potent anticancer drug with cardiotoxicity hampering its use. Neuropeptide Y (NPY) is the most abundant neuropeptide in the heart and a co-transmitter of the sympathetic nervous system that plays a role in cardiac diseases. The aim of this work was to study the impact of NPY on doxorubicin-induced cardiotoxicity. Transgenic mice overexpressing NPY in noradrenergic neurons (NPY-OED beta H) and wild-type mice were treated with a single dose of doxorubicin. Doxorubicin caused cardiotoxicity in both genotypes as demonstrated by decreased weight gain, tendency to reduced ejection fraction, and changes in the expression of several genes relevant to cardiac pathology. Doxorubicin resulted in a tendency to lower ejection fraction in NPY-OED beta H mice more than in wild-type mice. In addition, gain in the whole body lean mass gain was decreased only in NPY-OED beta H mice, suggesting a more severe impact of doxorubicin in this genotype. The effects of doxorubicin on genes expressed in the heart were similar between NPY-OED beta H and wild-type mice. The results demonstrate that doxorubicin at a relatively low dose caused significant cardiotoxicity. There were differences between NPY-OED beta H and wild-type mice in their responses to doxorubicin that suggest NPY to increase susceptibility to cardiotoxicity. This may point to the therapeutic implications as suggested for NPY system in other cardiovascular diseases.