Trastuzumab, the humanized monoclonal antibody specific for HER2 receptor, is the gold standard in the treatment of HER2+ breast cancer. Despite its high therapeutic efficacy, cardiotoxicity has emerged as a significant side effect. The molecular mechanisms involved are not well understood, but all converge on mitochondria. Mitochondrial Cx43 can confer cardioprotection by regulating mitochondrial calcium homeostasis, ROS production and propagation of apoptotic signals, and studies report that it is overexpressed both in ischemic preconditioning and in Doxorubicin-induced cardiotoxicity. This study was designed to evaluate whether mitochondrial Cx43 (mCx43) is also involved in Trastuzumab-induced cardiotoxicity. Here we demonstrated that mCx43 is overexpressed in Trastuzumab-treated H9c2 cells. Our data showed that inhibition of Cx43 translocation to mitochondria, obtained by radicicol pre-treatment, significantly increases cytosolic and mitochondrial superoxide formation, mitochondrial membrane depolarization and the consequent apoptosis induced by Trastuzumab. Our results support the hypothesis that disruption of mitochondrial function is the principal mechanism by which Trastuzumab elicits its cardiotoxicity and mCx43 appears to counteract the Trastuzumab-induced mitochondrial damage.

曲妥珠单抗（一种对HER2受体具有特异性的人源化单克隆抗体）是治疗HER2 +乳腺癌的金标准。尽管其具有很高的治疗功效，但心脏毒性已成为一种显着的副作用。涉及的分子机制尚不十分清楚，但都集中在线粒体上。线粒体Cx43可以通过调节线粒体钙稳态，ROS产生和凋亡信号的传播来赋予心脏保护作用，并且研究报告其在缺血预处理和阿霉素诱导的心脏毒性中均过表达。这项研究旨在评估线粒体Cx43（mCx43）是否也参与曲妥珠单抗引起的心脏毒性。在这里，我们证明了mCx43在曲妥珠单抗治疗的H9c2细胞中过表达。我们的数据表明，通过radicicol预处理获得的对Cx43易位至线粒体的抑制作用显着增加了胞质和线粒体超氧化物的形成，线粒体膜去极化以及由此导致的曲妥珠单抗的凋亡。我们的结果支持以下假设：线粒体功能的破坏是曲妥珠单抗引起其心脏毒性的主要机制，而mCx43似乎抵消了曲妥珠单抗引起的线粒体损伤。