Differential Roles of p38 MAPKs in Doxorubicin-induced cardiotoxicity

Doxorubicin (DOX) is a highly potent anti-cancer therapy agent. However, it has been associated with severe cardiotoxic effects that can results in fatal cardiomyopathies. Previous studies have identified the role of stress signaling pathways, particularly those involving p38 MAPKs in the development of cardiotoxicity. Four different isoforms of p38 MAPKs are expressed in the heart and they have been associated with differing functions. We hypothesized that p38 MAPKs have an isoform-specific role in DOX-induced cardiotoxicity. We tested this hypothesis in mice and human hearts. Fifteen (15w) and twenty-two (22w) week old mice – WT and with genetic deletion of p38a, p38b, p38g, p38d and p38gd MAPK were treated with either 20 or 30 mg/kg DOX or saline (vehicle) and their survival was tracked over 10 days. Cardiac function was assessed using echocardiography and electrocardiography. Age-, sex-, dose- and p38 MAPK-specific survival responses were studied in these mice. Specifically, while saline-treatment did not influence survival of mice in any group, DOX treatment resulted in varying survival rates in WT mice, with the lowest survival rate observed in 15w male and female mice treated with 30 mg/kg DOX. Interestingly, among young, male p38 mutant mice treated with DOX, survival rates were lower relative to saline treated controls, but not different relative to DOX-treated WT. However, among young, female p38 mutant mice treated with DOX, low survival rates were observed in p38b, p38g and p38gd knockout (KO) relative to saline-treated controls; while p38d and p38b KO had higher and lower survival rates, respectively, relative to DOX-treated WT. Survival rates correlated with improved cardiac mechanical and electrical function in p38a and p38d KO mice, respectively. Next, we treated human cardiac slices with DOX (0 – 50mM) or DOX (5mM) + SB203580 (p38a and p38b inhibitor, 5mM) or DOX (5mM) + Compound 62 (pan p38 MAPK inhibitor, 1mM). Dose-dependent slowing of conduction velocity (CV) was observed in human slices treated with DOX. SB203580 failed to prevent DOX-induced CV slowing while Compound 62 rescued CV during DOX treatment. These data indicate the differential roles of individual p38 MAPK isoforms in cardiotoxicity development due to DOX treatment. While deleting p38a or p38d isoforms prevented cardiotoxicity, deleting p38b promoted it in female mice. Therefore, blocking p38a and/or p38d may be advantageous to prevent DOX-induced cardiotoxicity