Emergency and Critical Care Center, Intensive Care Unit, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, China.
Emergency and Critical Care Center, Department of Emergency Medicine, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, China.
Cardiovasc Toxicol. 2022 Nov;22(10-11):879-891. doi: 10.1007/s12012-022-09766-2. Epub 2022 Aug 5.
As a widely used anti-tumor anthracycline, the accumulation of Doxorubicin (DOX) in body causes irreparable cardiomyocyte damage and therefore is limited in clinical application. Strategies to prevent from DOX-associated cardiotoxicity are urgent for patients who undergo DOX-based chemotherapy. Since oxidative stress injury being the major reason for myocardial toxicity of DOX, here we demonstrated that, Alpha-lipoic acid (ALA), which is a reductive agent, plays a cardioprotective role in attenuating DOX-induced cardiotoxicity by inhibiting pyruvate dehydrogenase kinase 4 (PDK4) expression. In vivo, the beneficial effect of ALA was evidenced by increased survival rate, mechanical contraction, and oxidative phosphorylation, while decreased reactive oxidative species (ROS) and apoptosis. In vitro, PDK4 overexpression remarkably increased DOX-induced apoptosis and ROS production in H9C2 cells. Notably, the protective effect of ALA was abrogated by PDK4 overexpression. We further used PDK4 knockout mice to identify the role of PDK4 in DOX-induced cardiotoxicity. Results elicited that PDK4 deficiency showed a consistent effect in protecting DOX cardiotoxicity as ALA treatment, which was evidenced by restored redox homeostasis and mitochondrial metabolism, finally inhibited myocardial injury. In conclusion, the cardioprotective role of ALA against DOX cardiotoxicity was dependent on PDK4-mediated regulation of oxidative stress and mitochondria metabolism.
阿霉素（DOX）作为一种广泛应用的抗肿瘤蒽环类药物，其在体内的积累会导致不可逆转的心肌细胞损伤，因此在临床应用中受到限制。对于接受 DOX 化疗的患者，预防 DOX 相关心脏毒性的策略迫在眉睫。由于氧化应激损伤是 DOX 导致心肌毒性的主要原因，我们在这里证明，作为一种还原剂的α-硫辛酸（ALA）通过抑制丙酮酸脱氢酶激酶 4（PDK4）的表达，在减轻 DOX 诱导的心脏毒性方面发挥了心脏保护作用。在体内，ALA 的有益作用表现为存活率、机械收缩和氧化磷酸化增加，而活性氧（ROS）和细胞凋亡减少。在体外，PDK4 的过表达显著增加了 H9C2 细胞中 DOX 诱导的细胞凋亡和 ROS 产生。值得注意的是，PDK4 的过表达会削弱 ALA 的保护作用。我们进一步使用 PDK4 敲除小鼠来确定 PDK4 在 DOX 诱导的心脏毒性中的作用。结果表明，PDK4 缺乏在保护 DOX 心脏毒性方面表现出一致的作用，与 ALA 治疗一样，这表现在氧化还原平衡和线粒体代谢得到恢复，最终抑制了心肌损伤。总之，ALA 对 DOX 心脏毒性的心脏保护作用依赖于 PDK4 介导的氧化应激和线粒体代谢的调节。
