Anthracycline cardiotoxicity is exacerbated by global p38β genetic ablation in a sexually dimorphic manner but unaltered by cardiomyocyte-specific p38α loss
Document Type
Journal Article
Publication Date
11-1-2023
Journal
American journal of physiology. Heart and circulatory physiology
Volume
325
Issue
5
DOI
10.1152/ajpheart.00458.2023
Keywords
cardiotoxicity; doxorubicin; p38α/MAPK14; p38β/MAPK11; sexual dimorphism
Abstract
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 p38δ deletion protected female but not male mice from DIC, whereas global p38γ deletion did not significantly modulate it. Here we studied the in vivo roles of p38α and p38β in acute DIC. Male and female mice with cardiomyocyte-specific deletion of p38α or global deletion of p38β 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 p38β deletion significantly aggravated DIC and worsened cardiac electrical and mechanical function deterioration in female mice. Mechanistically, DIC in p38β-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 p38α 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 p38α and p38β MAPKs in DOX-induced cardiac injury and suggest a novel in vivo function of p38β in protecting female mice from DIC. We show that p38α and p38β have distinct in vivo functions in a murine model of acute DIC. Specifically, although conditional cardiomyocyte-specific p38α deletion exhibited mild cardioprotective effects in male mice, p38β deletion exacerbated the DOX cardiotoxicity in female mice. Our findings caution against employing pyridinyl imidazole inhibitors that target both p38α and p38β isoforms as a cardioprotective strategy against DIC. Such an approach could have undesirable sex-dependent effects, including attenuating p38β-dependent cardioprotection in females.
APA Citation
George, Sharon A.; Kiss, Alexi; Trampel, Katy Anne; Obaid, Sofian N.; Tang, Lichao; Efimov, Igor R.; and Efimova, Tatiana, "Anthracycline cardiotoxicity is exacerbated by global p38β genetic ablation in a sexually dimorphic manner but unaltered by cardiomyocyte-specific p38α loss" (2023). GW Authored Works. Paper 3893.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/3893
Department
Anatomy and Regenerative Biology