Bradykinin receptor participates in doxorubicin-induced cardiotoxicity by modulating iNOS signal pathway.

Doxorubicin (DOX), an effective and broad-spectrum anthracycline antibiotic, is widely used in the treatment of numerous malignancies. However, dose-dependent cardiotoxicity limits the clinical application of DOX, and the molecular mechanisms are still unknown. In this study, we used the BK receptor B1/B2 double-knockout (B1B2 -/- ) mice to observe the role of BK receptor in cardiotoxicity induced by DOX and the underlying mechanisms. DOX induced myocardial injury with increased serum levels of AST, CK, and LDH, upregulated tissue expression of bradykinin B1/B2 receptor, FABP4 and iNOS, and downregulated expression of eNOS. However, these altered releases of myocardial enzyme and the expression level of iNOS were significantly prevented in the B1B2-/- mice. We concluded that the activation of both B1 and B2 receptors of BK were involved in the DOX-induced acute myocardial injury, possibly mediated through iNOS signaling pathways.