Anthracycline cardiotoxicity is exacerbated by global p38β genetic ablation in a sexually dimorphic manner but unaltered by cardiomyocyte-specific p38α loss

Severe cardiotoxic effects limit the efficacy of doxorubicin (DOX) as a chemotherapeutic agent. Activation of intracellular stress signaling networks, including p38 mitogen-activated protein kinase (MAPK), has been implicated in DOX-induced cardiotoxicity (DIC). However, the roles of the individual p38 isoforms in DIC remain incompletely elucidated. We recently reported that global p38 delta deletion protected female but not male mice from DIC, whereas global p38 gamma deletion did not significantly modulate it. Here we studied the in vivo roles of p38 alpha and p38 beta in acute DIC. Male and female mice with cardiomyocyte-specific deletion of p38 alpha or global deletion of p38 beta and their wild-type counterparts were injected with DOX. Survival and health were tracked for 10 days postinjection. Cardiac function was assessed by echocardiography and electrocardiography and fibrosis by Picrosirius red staining. Expression and activation of signaling proteins and inflammatory markers were measured by Western blot, phosphorylation array, and chemokine/cytokine array. Global p38 beta deletion significantly aggravated DIC and worsened cardiac electrical and mechanical function deterioration in female mice. Mechanistically, DIC in p38 beta-null female mice correlated with increased autophagy, sustained hyperactivation of proapoptotic JNK signaling, as well as remodeling of a myocardial inflammatory environment. In contrast, cardiomyocyte-specific deletion of p38 alpha improved survival of DOX30-treated male mice 5 days posttreatment but did not influence cardiac function in DOX-treated male or female mice. Our data highlight the sex- and isoform-specific roles of p38 alpha and p38 beta MAPKs in DOX-induced cardiac injury and suggest a novel in vivo function of p38 beta in protecting female mice from DIC.

Automated summary

This study reveals the sex- and isoform-specific roles of p38 MAPKs in DOX-induced cardiac injury. Global p38 beta deletion aggravated DIC and worsened cardiac function deterioration, while cardiomyocyte-specific p38 alpha deletion improved survival of male mice. These findings have important implications for understanding and treating DIC.