阿霉素诱发的心肌病的发病机制仍不清楚。本研究的目的是检验我们的假设，即 ADAM17 会加重阿霉素诱导的心肌细胞凋亡，而抑制 ADAM17 可能会改善阿霉素诱导的心肌病。 C57BL/6J小鼠腹腔注射累积剂量的阿霉素以诱导心肌病。产生了心肌细胞特异性 ADAM17 敲除 (A17α-MHCKO) 和 ADAM17 过表达 (AAV9-oeA17) 小鼠。此外，还对不同小鼠组的心脏组织进行了RNA测序，并对接受不同处理的新生大鼠心肌细胞（NRCM）进行了体外实验。在 A17fl/fl 和 A17α-MHCKO 小鼠中构建小鼠肿瘤模型。此外，还生成了心肌细胞特异性 TRAF3 敲低和 TRAF3 过表达小鼠。在阿霉素处理的小鼠心脏和 NRCM 中，ADAM17 的表达和活性显着上调。 A17α-MHCKO 小鼠阿霉素诱导的心肌细胞凋亡较 A17fl/fl 小鼠少，且心肌细胞 ADAM17 缺乏并不影响阿霉素的抗肿瘤作用。相反，在阿霉素治疗后，AAV9-oeA17小鼠相对于AAV9-oeNC小鼠表现出明显加重的心肌细胞凋亡。从机制上讲，阿霉素增强转录因子C/EBPβ的表达，导致心肌细胞中ADAM17的表达和活性增加，从而增强TNF-α的脱落并上调TRAF3的表达。 TRAF3增加促进TAK1自身磷酸化，导致MAPKs通路激活和心肌细胞凋亡。 ADAM17 通过上调 TRAF3/TAK1/MAPKs 信号传导，作为阿霉素诱导的心肌细胞凋亡、心脏重塑和功能障碍的正调节因子。因此，靶向 ADAM17/TRAF3/TAK1/MAPKs 信号传导在治疗阿霉素诱导的心脏毒性方面具有广阔的前景。© 2024。作者。

The pathogenesis of doxorubicin-induced cardiomyopathy remains unclear. This study was carried out to test our hypothesis that ADAM17 aggravates cardiomyocyte apoptosis induced by doxorubicin and inhibition of ADAM17 may ameliorate doxorubicin-induced cardiomyopathy. C57BL/6J mice were intraperitoneally injected with a cumulative dose of doxorubicin to induce cardiomyopathy. Cardiomyocyte-specific ADAM17-knockout (A17α-MHCKO) and ADAM17-overexpressing (AAV9-oeA17) mice were generated. In addition, RNA sequencing of the heart tissues in different mouse groups and in vitro experiments in neonatal rat cardiomyocytes (NRCMs) receiving different treatment were performed. Mouse tumor models were constructed in A17fl/fl and A17α-MHCKO mice. In addition, cardiomyocyte-specific TRAF3-knockdown and TRAF3-overexpressing mice were generated. ADAM17 expression and activity were markedly upregulated in doxorubicin-treated mouse hearts and NRCMs. A17α-MHCKO mice showed less cardiomyocyte apoptosis induced by doxorubicin than A17fl/fl mice, and cardiomyocyte ADAM17 deficiency did not affect the anti-tumor effect of doxorubicin. In contrast, AAV9-oeA17 mice exhibited markedly aggravated cardiomyocyte apoptosis relative to AAV9-oeNC mice after doxorubicin treatment. Mechanistically, doxorubicin enhanced the expression of transcription factor C/EBPβ, leading to increased expression and activity of ADAM17 in cardiomyocyte, which enhanced TNF-α shedding and upregulated the expression of TRAF3. Increased TRAF3 promoted TAK1 autophosphorylation, resulting in activated MAPKs pathway and cardiomyocyte apoptosis. ADAM17 acted as a positive regulator of cardiomyocyte apoptosis and cardiac remodeling and dysfunction induced by doxorubicin by upregulating TRAF3/TAK1/MAPKs signaling. Thus, targeting ADAM17/TRAF3/TAK1/MAPKs signaling holds a promising potential for treating doxorubicin-induced cardiotoxicity.© 2024. The Author(s).