Maraviroc ameliorates doxorubicin-induced atrioventricular block through blocking CCL5-CCR5 interaction in macrophage-cardiomyocyte axis

Doxorubicin (Dox)-induced cardiotoxicity (DIC) remains a challenge in tumor chemotherapy. Targeting macrophage-secreted molecules is a potential strategy to mitigate DIC. Transcriptome analysis of RAW264.7 cells treated with 100 nM Dox revealed increases in 33 proteins located in the extracellular space, including CCL5. An animal model of DIC characterized by degree I atrioventricular block was established in 9-12 weeks old male C57BL/6 mice through three doses of 5 mg/kg Dox intraperitoneally (i.p.) administered every third day. The plasma CCL5 level in these mice consistently increased, which could be attenuated by macrophage depletion using clodronate liposome (15 mg/kg, i. p.). In pharmacological experiments with these animals, administration of maraviroc (MVC) (50 mg/kg, i. p., daily) prevented PR interval elongation caused by Dox. Both in vitro and in vivo experiments showed that MVC attenuated Ca