DDR2 deficiency attenuates doxorubicin-induced cardiotoxicity by reducing cardiac dysfunction and oxidative stress in mice.

Doxorubicin (DOX) is a highly effective anthracycline chemotherapeutic drug. However, the clinical application is limited due to its dose-dependent cardiotoxicity. Discoidin domain receptor 2 (DDR2), the main collagen-binding receptor tyrosine kinase is a major player of various degrees of fibrosis or tissue restructuring in pathological conditions and unknown its role for DOX-induced heart injuries. We investigated the impacts of DDR2 deficiency from acute DOX cardiotoxicity in vivo, by utilizing DDR2-knockout (DDR2KO) and wild-type (Wt) mice. Genetic deletion of DDR2 significantly reduced DOX-induced cardiac dysfunction. Furthermore, we observed a substantial reduction in reactive oxygen species generation within the vasculature of DDR2KO + DOX mice, along with decreased mRNA expression of Hmox1 and Nfe2l2 in cardiac tissue. Additionally, DDR2 deficiency suppressed the DOX-induced Inflammatory cytokines. Finally, DDR2KO attenuated DOX-induced cardiac fibrosis. The work demonstrates that DDR2 plays a pivotal role in the pathogenesis of DOX-mediated cardiotoxicity.