Abstract P155: HSF-1 Deletion Induces MDR1 Gene in the Heart and Protects from Doxorubicin-Induced Cardiotoxicity
Heat shock factor 1 (HSF-1) has been found to be a frontline responder of different stresses in eukaryotic cells. Deletion of HSF-1 has been reported to develop defects in mice. In the present work we report that deletion of HSF-1 induced multidrug resistance 1 (MDR1) gene and P-glycoprotein (P-gp) expression. Both RT-PCR and western blotting, confirmed the higher level of MDR1 gene expression and P-gp protein in HSF-1 knock out mouse hearts. P-gp is well known ATP binding cassette, which extrudes intracellular drugs upon binding ATP. Hence the phenotype of the P-gp pump in HSF-1−/− mice was studied in the form of Doxorubicin (Dox) extrusion in the heart. Cardiomyocytes isolated from HSF-1−/− and HSF-1+/− mice retained very less intracellular Dox, compared to wild type counterparts. Similarly, both HSF-1+/− and HSF-1−/− mice were less susceptible for Dox-induced cardiotoxicity, as seen from reduced cardiac dysfunction in these group against Dox (as confirmed by cardiac MRI and echocardiography). Further confirmatory studies revealed that deletion of HSF-1 enhances NF-B, which subsequently induces MDR1 gene. These results reveal that inactivation of HSF-1 in the heart will be a potential approach to prevent Dox-induced cardiotoxicity.
- © 2011 by American Heart Association, Inc.