| First Author | George SA | Year | 2020 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 319 |
| Issue | 4 | Pages | H775-H786 |
| PubMed ID | 32822209 | Mgi Jnum | J:298508 |
| Mgi Id | MGI:6480196 | Doi | 10.1152/ajpheart.00415.2020 |
| Citation | George SA, et al. (2020) p38delta genetic ablation protects female mice from anthracycline cardiotoxicity. Am J Physiol Heart Circ Physiol 319(4):H775-H786 |
| abstractText | The efficacy of an anthracycline antibiotic doxorubicin (DOX) as a chemotherapeutic agent is limited by dose-dependent cardiotoxicity. DOX is associated with activation of intracellular stress signaling pathways including p38 MAPKs. While previous studies have implicated p38 MAPK signaling in DOX-induced cardiac injury, the roles of the individual p38 isoforms, specifically, of the alternative isoforms p38gamma and p38delta, remain uncharacterized. We aimed to determine the potential cardioprotective effects of p38gamma and p38delta genetic deletion in mice subjected to acute DOX treatment. Male and female wild-type (WT), p38gamma(-/-), p38delta(-/-), and p38gamma(-/-)delta(-/-) mice were injected with 30 mg/kg DOX and their survival was tracked for 10 days. During this period, cardiac function was assessed by echocardiography and electrocardiography and fibrosis by Picro Sirius Red staining. Immunoblotting was performed to assess the expression of signaling proteins and markers linked to autophagy. Significantly improved survival was observed in p38delta(-/-) female mice post-DOX relative to WT females, but not in p38gamma(-/-) or p38gamma(-/-)delta(-/-) male or female mice. The improved survival in DOX-treated p38delta(-/-) females was associated with decreased fibrosis, increased cardiac output and LV diameter relative to DOX-treated WT females, and similar to saline-treated controls. Structural and echocardiographic parameters were either unchanged or worsened in all other groups. Increased autophagy, as suggested by increased LC3-II level, and decreased mammalian target of rapamycin activation was also observed in DOX-treated p38delta(-/-) females. p38delta plays a crucial role in promoting DOX-induced cardiotoxicity in female mice by inhibiting autophagy. Therefore, p38delta targeting could be a potential cardioprotective strategy in anthracycline chemotherapy.NEW & NOTEWORTHY This study for the first time identifies the sex-specific roles of the alternative p38gamma and p38delta MAPK isoforms in promoting doxorubicin (DOX) cardiotoxicity. We show that p38delta and p38gamma/delta systemic deletion was cardioprotective in female but not in male mice. Cardiac structure and function were preserved in DOX-treated p38delta(-/-) females and autophagy marker was increased. |
