Anthracycline cardiotoxicity is exacerbated by global p38b genetic ablation in a sexually dimorphic manner but unaltered by cardiomyocyte-specific p38a loss

Sharon A. George, Alexi Kiss, Katy Anne Trampel, Sofian N. Obaid, Lichao Tang, Igor R. Efimov, Tatiana Efimova

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 p38d deletion protected female but not male mice from DIC, whereas global p38c deletion did not significantly modulate it. Here we studied the in vivo roles of p38a and p38b in acute DIC. Male and female mice with cardiomyocyte-specific deletion of p38a or global deletion of p38b 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 p38b deletion significantly aggravated DIC and worsened cardiac electrical and mechanical function deterioration in female mice. Mechanistically, DIC in p38b-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 p38a 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 p38a and p38b MAPKs in DOX-induced cardiac injury and suggest a novel in vivo function of p38b in protecting female mice from DIC. NEW & NOTEWORTHY We show that p38a and p38b have distinct in vivo functions in a murine model of acute DIC. Specifically, although conditional cardiomyocyte-specific p38a deletion exhibited mild cardioprotective effects in male mice, p38b deletion exacerbated the DOX cardiotoxicity in female mice. Our findings caution against employing pyridinyl imidazole inhibitors that target both p38a and p38b isoforms as a cardioprotective strategy against DIC. Such an approach could have undesirable sex-dependent effects, including attenuating p38b-dependent cardioprotection in females.

Original languageEnglish (US)
Pages (from-to)H983-H997
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume325
Issue number5
DOIs
StatePublished - Nov 2023

Keywords

  • cardiotoxicity
  • doxorubicin
  • p38a/MAPK14
  • p38b /MAPK11
  • sexual dimorphism

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

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