Diminished molecular response to doxorubicin and loss of cardioprotective effect of dexrazoxane in Egr-1 deficient female mice

Doxorubicin (DOX) and VP16 are DNA topoisomerase II inhibitors yet only DOX induces an irreversible cardiotoxicity, likely through DOX-induced oxidati ve stress. Egr-1 is overexpressed after many stimuli that increase oxidativ e stress in vitro and after DOX-injection into adult mice in vivo. To inves tigate Egr-1 function in the heart, we compared the molecular and histologi cal responses of wild type (+/+) and Egr-1 deficient (-/-) female mice to s aline, DOX, VP16, the cardioprotectant dexrazoxane (DZR), or DOX+DZR inject ion. DOX, and to a lesser extent VP16, induced characteristic increases in cardiac muscle and non-muscle genes typical of cardiac damage in +/+ mice, whereas only beta-MHC and Sp1 were increased in -/- mice. DZR-alone treated +/+ mice showed increased cardiomyocyte transnuclear width without a chang e to the heart to body weight (HW/BW) ratio. However, DZR-alone treated -/- mice had an increased HW/BW, increased cardiomyocyte transnuclear width, a nd gene expression changes similar to DOX-injected +/+ mice. DZR pre-inject ion alleviated DOX-induced gene changes in +/+ mice; in DZR+DOX injected -/ - mice the increases in cardiac and non-muscle gene expression were equal t o, or exceeded that, detected after DOX-alone or DZR-alone injections. We c onclude that Egr-1 is required for DOX-induced molecular changes and for DZ R-mediated cardioprotection.