Department of Biomedical Engineering, Northwestern University, Chicago, Illinois, United States.
Department of Biomedical Engineering, George Washington University, Washington, District of Columbia, United States.
Am J Physiol Heart Circ Physiol. 2023 Nov 1;325(5):H983-H997. doi: 10.1152/ajpheart.00458.2023. Epub 2023 Aug 25.
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.
严重的心脏毒性作用限制了多柔比星（DOX）作为化疗药物的疗效。细胞内应激信号网络的激活，包括 p38 丝裂原活化蛋白激酶（MAPK），已被牵连到 DOX 诱导的心脏毒性（DIC）中。然而，个体 p38 同工型在 DIC 中的作用仍不完全清楚。我们最近报道，全局 p38δ 缺失可保护雌性小鼠免受 DIC 的影响，但全局 p38γ 缺失则不能显著调节 DIC。在这里，我们研究了 p38α 和 p38β 在急性 DIC 中的体内作用。用 DOX 注射具有心肌细胞特异性 p38α 缺失或全局 p38β 缺失的雄性和雌性小鼠及其野生型对照小鼠，并在注射后 10 天跟踪其生存和健康状况。通过超声心动图和心电图评估心脏功能，并通过 Picrosirius 红染色评估纤维化。通过 Western blot、磷酸化阵列和趋化因子/细胞因子阵列测量信号蛋白和炎症标志物的表达和激活。全局 p38β 缺失显著加重 DIC，并使雌性小鼠心脏电和机械功能恶化。从机制上讲，p38β 缺失雌性小鼠的 DIC 与自噬增加、促凋亡 JNK 信号持续过度激活以及心肌炎症环境重塑有关。相比之下，心肌细胞特异性 p38α 缺失可提高 DOX30 治疗后 5 天雄性小鼠的存活率，但不影响 DOX 治疗的雄性或雌性小鼠的心脏功能。我们的数据突出了 p38α 和 p38β MAPK 在 DOX 诱导的心脏损伤中的性别和同工型特异性作用，并表明 p38β 在保护雌性小鼠免受 DIC 中的新的体内功能。我们表明，p38α 和 p38β 在急性 DIC 的小鼠模型中具有不同的体内功能。具体而言，尽管条件性心肌细胞特异性 p38α 缺失在雄性小鼠中表现出轻度的心脏保护作用，但 p38β 缺失加剧了雌性小鼠的 DOX 心脏毒性。我们的发现警告不要将靶向 p38α 和 p38β 同工型的吡啶基咪唑抑制剂作为对抗 DIC 的心脏保护策略。这种方法可能会产生不良的性别依赖性影响，包括削弱雌性中 p38β 依赖性的心脏保护作用。
