PEX1 is a mediator of α1‐adrenergic signaling attenuating doxorubicin‐induced cardiotoxicity

Doxorubicin (DOX) is a potent chemotherapeutic agent used for cancer treatment, however, DOX-induced cardiotoxicity is a serious clinical problem because it causes acute and chronic heart dysfunction. Many studies have indicated that the α1-adrenergic receptor protects the heart from pathologic stress through activation survival signaling, however, the mechanism remains largely unknown. Previous studies have detected that the phenylephrine-induced complex-1 (PEX1) transcription factor, also known as zinc-finger protein 260 (Zfp260), is an effector of α1-adrenergic signaling in cardiac hypertrophy. Our present study aimed to investigate the role and underlying mechanism of PEX1 in cardiomyocyte survival during DOX-induced cardiotoxicity. Mice were exposed to a single intraperitoneal injection of DOX (15 mg/kg) to generate DOX-induced cardiotoxicity. We found that PEX1 expression was downregulated in DOX-treated murine hearts. PEX1 deficiency resulted in increased apoptosis, and conversely, PEX1 overexpression alleviated apoptosis induced by DOX in primary cardiomyocytes, as well as upregulated antiapoptotic genes such as BCL-2 and BCL-XL. Mechanistically, we identified that PEX1 might exert its antiapoptosis effect by playing a pivotal role in the action of α1-adrenergic signaling activation, which depends on the presence of GATA-4. Based on these findings, we supposed that PEX1 may be a novel transcription factor involved in cardiac cell survival and a promising candidate target for DOX-induced cardiotoxicity.