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p38delta genetic ablation protects female mice from anthracycline cardiotoxicity
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p38delta genetic ablation protects female mice from anthracycline cardiotoxicity
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p38delta genetic ablation protects female mice from anthracycline cardiotoxicity
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Paper
p38delta genetic ablation protects female mice from anthracycline cardiotoxicity
2020
Overview
BACKGROUND: 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. OBJECTIVES: To determine the potential cardioprotective effects of p38gamma and p38delta genetic deletion in mice subjected to acute DOX treatment. METHODS: 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 ten days. During this period cardiac function was assessed by echocardiography and electrocardiography and fibrosis by PicroSirius Red staining. Immunoblotting was performed to assess the expression of signaling proteins and markers linked to autophagy. RESULTS: 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 evidenced by increased LC3-II level, and decreased mTOR activation was also observed in DOX-treated p38delta-/- females. CONCLUSIONS: 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.
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