Smad3 Promotes Adverse Cardiovascular Remodeling and Dysfunction in Doxorubicin Treated Hearts.

Many anticancer therapies cause serious cardiovascular complications that degrade quality of life and cause early mortality in treated patients. Specifically, doxorubicin is known as an effective anticancer agent that causes cardiomyopathy in treated patients. There has been growing interest in defining the role of endothelial cells in cardiac damage by doxorubicin. We have shown in the present study that endothelial nuclei accumulate more intravenously administered doxorubicin than other cardiac cell types. Doxorubicin enhanced cardiac production of the TGF-b ligands and nuclear translocation of phospho-Smad3 in both cultured and in vivo cardiac endothelial cells. In order to examine the role of the TGF-b/Smad3 pathway in cardiac damage by doxorubicin, we utilized both Smad3 shRNA stable endothelial cell lines and Smad3 knockout mice. We demonstrated that upregulation of the TGF-b and inflammatory cytokine/cytokine receptor pathways as well as suppression of cell cycle and angiogenesis by doxorubicin were alleviated in Smad3 deficient endothelial cells. Similarly, increased cardiac expression of cytokines and chemokines observed in treated wild-type mice was diminished in treated Smad3 knockout animals. We also observed left ventricular remodeling and depressed systolic function in doxorubicin treated wild-type but not Smad3 knockout mice. This work provides evidence for the critical role of the canonical TGF-b/Smad3 pathway in cardiac damage by doxorubicin.