Aims Doxorubicin (DXR) is a chemotherapeutic agent that causes dose-dependent cardiotoxicity. Recently it has been proposed that the NADase CD38 may play a role in doxorubicin-induced cardiotoxicity (DIC). CD38 is the main NAD+-catabolizing enzyme in mammalian tissues. Interestingly, in the heart, CD38 is mostly expressed as an ecto-enzyme that can be targeted by specific inhibitory antibodies. The goal of the present study is to characterize the role of CD38 ecto-enzymatic activity in cardiac metabolism and the development of DIC. Method and Results Using both a transgenic animal model and a non-cytotoxic enzymatic anti-CD38 antibody we investigated the role of CD38 and its ecto-NADase activity in DIC in pre-clinical models. First, we observed that DIC was prevented in the CD38 catalytically inactive (CD38 CI) transgenic mice. Both left ventricular systolic function and exercise capacity were decreased in WT but not in CD38CI mice treated with DXR. Second, blocking CD38 NADase activity with the specific antibody 68 (Ab68) likewise protected mice against DIC and decreased DXR-related mortality by 50%. Reduction of DXR-induced mitochondrial dysfunction, energy deficiency, and inflammation gene expression were identified as the main mechanisms mediating the protective effects. Conclusions NAD+-preserving strategies by inactivation of CD38 via a genetic or a pharmacological-based approach improve cardiac energetics and reduce cardiac inflammation and dysfunction otherwise seen in an acute DXR cardiotoxicity model. Translational perspective Specific and non-cytotoxic ecto-NADase anti-CD38 antibodies may be a potential therapy for anthracyclines-induced cardiac dysfunction.

中文翻译：

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Ecto-CD38-NADase 抑制调节心脏代谢并保护小鼠免受阿霉素诱导的心脏毒性

目的 多柔比星 (DXR) 是一种化疗药物，可引起剂量依赖性心脏毒性。最近有人提出 NADase CD38 可能在阿霉素诱导的心脏毒性 (DIC) 中发挥作用。CD38 是哺乳动物组织中主要的 NAD+ 分解代谢酶。有趣的是，在心脏中，CD38 主要表达为一种胞外酶，可以被特异性抑制抗体靶向。本研究的目的是表征 CD38 胞外酶活性在心脏代谢和 DIC 发展中的作用。方法和结果使用转基因动物模型和非细胞毒性酶抗 CD38 抗体，我们研究了临床前模型中 DIC 中 CD38 及其胞外 NAD 酶活性的作用。首先，我们观察到 CD38 催化失活 (CD38 CI) 转基因小鼠的 DIC 得到了预防。WT 小鼠的左心室收缩功能和运动能力均下降，但 DXR 治疗的 CD38CI 小鼠则没有。其次，用特异性抗体 68 (Ab68) 阻断 CD38 NADase 活性同样可以保护小鼠免受 DIC 的侵害，并将 DXR 相关死亡率降低 50%。DXR 诱导的线粒体功能障碍、能量缺乏和炎症基因表达的减少被确定为介导保护作用的主要机制。结论 通过遗传或药理学方法灭活 CD38 的 NAD+ 保留策略可改善心脏能量并减少急性 DXR 心脏毒性模型中出现的心脏炎症和功能障碍。转化视角 特异性和非细胞毒性的胞外 NAD 酶抗 CD38 抗体可能是治疗蒽环类药物引起的心功能障碍的潜在疗法。