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 Ca2+ overload induced by CCL5 in H9C2 cells and by Dox in cardiomyocytes from DIC models. Further in vitro experiments confirmed that CCL5 decreases the SERCA2a level and PKA-C, PLB phosphorylation in H9C2 cells, exacerbating Ca2+ overload and CaMKII phosphorylation, which can be attenuated by MVC administration. In conclusion, Dox can induce an increase in macrophage-derived CCL5 in plasma, and MVC targeting the CCL5's receptor CCR5 can ameliorate atrioventricular block caused by Dox toxicity, suggesting that it may be a candidate for DIC treatment in chemotherapy.