Rab10 protects against DOX-induced cardiotoxicity by alleviating the oxidative stress and apoptosis of cardiomyocytes.

Doxorubicin (DOX) is a widely used anticancer drug, but its clinical application is limited by cardiotoxicity. As a member of the Rab family, Rab10 has multiple subcellular localizations and carries out a wide variety of functions. Here, we explored the role of Rab10 on DOX-induced cardiotoxicity. Cardiac-specific Rab10 transgenic mice were constructed and treated with DOX or saline. We found that cardiac-specific overexpression of Rab10 alleviated cardiac dysfunction and attenuated cytoplasmic vacuolization and mitochondrial damage in DOX-treated mouse heart tissues. Immunofluorescence staining and Western blot analysis showed that Rab10 alleviated DOX-induced apoptosis and oxidative stress in cardiomyocytes in mouse heart tissues. We demonstrated that DOX mediated apoptosis, oxidative stress and depolarization of the mitochondrial membrane potential in H9c2 cells, while overexpression and knockdown of Rab10 attenuated and aggravated these effects, respectively. Furthermore, we found that Mst1, a serine-threonine kinase, was cleaved and translocated into the nucleus in H9c2 cells after DOX treatment, and knockdown of Mst1 alleviated DOX-induced cardiomyocyte apoptosis. Overexpression of Rab10 inhibited the cleavage of Mst1 mediated by DOX treatment in vivo and in vitro. Together, our findings demonstrated that cardiac-specific overexpression of Rab10 alleviated DOX-induced cardiac dysfunction and injury via inhibiting oxidative stress and apoptosis of cardiomyocytes, which may be partially ascribed to the inhibition of Mst1 activity.