Abstract
Introduction: Doxorubicin (DOX) is currently one of the most used anthracycline anticancer drugs. However, the cardiotoxicity of DOX limits its application in cancer patients. Cellular repressor of E1A-stimulated genes (CREG1) is an important cardioprotective factor. Hypothesis: We investigated the underlying effects and mechanism of of CREG1 in DOX-induced cardiotoxicity have not been reported. Methods: In vivo, a mouse DOX-induced cardiotoxicity model was established by DOX intraperitoneal injection, the mRNA and protein expression of CREG1 in the myocardium was examined using real-time PCR and western blot. CREG1 transgenic mice and cardiac-specific CREG1 knockout mice were used to establish DOX-induced cardiotoxicity model. HE staining, Masson staining, WGA staining and western blot were applied to examine fibrosis, myocardial hypertrophy and ferroptosis. In vitro, neonatal mouse cardiomyocytes (NMCMs) were stimulated with DOX, CREG1 overexpression adenovirus and small interfering RNA was used to examine the role of CREG1 on the ferroptosis of NMCMs. Results: In vivo, the mRNA and protein expression of CREG1 were significantly reduced in DOX-treated myocardium. CREG1 overexpression alleviated the myocardial damage induced by DOX, and CREG1 deficiency aggravated the DOX-induced cardiotoxicity. The abnormal increase in ferroptosis was shown in the DOX-treated heart tissues. CREG1 overexpression inhibited the ferroptosis, and CREG1 deficiency aggravated the ferroptosis induced by DOX. In vitro, the mRNA and protein of CREG1 was reduced in DOX-treated NMCMs. CREG1 overexpression reduced the ferroptosis of cardiomyocytes, CREG1 knockdown aggravated the ferroptosis of cardiomyocytes induced by DOX. Mechanically, CREG1 inhibited the mRNA and protein expression of pyruvate dehydrogenase kinase 4 (PDK4). The effect of CREG1 overexpression on ferroptosis of cardiomyocytes was reversed by PDK4 overexpression. Conclusion: CREG1 alleviated DOX-induced cardiotoxicity by inhibiting ferroptosis of cardiomyocytes. Our findings might help clarify new roles of CREG1 in the development of DOX-induced cardiotoxicity.
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