CCPG1-driven ER-phagy was activated by doxorubicin, and its ablation in preclinical models exacerbated doxorubicin-induced apoptosis and systolic dysfunction.
Does CCPG1-driven ER-phagy protect cardiomyocytes from doxorubicin-induced cardiotoxicity?
CCPG1-driven ER-phagy plays a compensatory role in reducing doxorubicin-induced cardiotoxicity, suggesting it may be a potential therapeutic target.
Background: The administration of anthracycline drugs induces progressive and dose-related cardiac damage through several cytotoxic mechanisms, including endoplasmic reticulum (ER) stress. The unfolded protein response plays a crucial role for mitigating misfolded protein accumulation induced by excessive ER stress. Objectives: We aimed to clarify whether endoplasmic reticulum-selective autophagy machinery (ER-phagy) serves as an alternative system to protect cardiomyocytes from ER stress caused by anthracycline drugs. Methods: Primary cultured cardiomyocytes, H9c2 cell lines, and cardiomyocyte-specific transgenic mice, all expressing ss-RFP-GFP-KDEL proteins, were used as ER-phagy reporter models. We generated loss-of-function models using RNA interference or gene-trap mutagenesis techniques. We assessed phenotypes and molecular signaling pathways using immunoblotting, quantitative polymerase chain reaction, cell viability assays, immunocytochemical and histopathological analyses, and cardiac ultrasonography. Results: The administration of doxorubicin (Dox) activated ER-phagy in ss-RFP-GFP-KDEL-transduced cardiomyocytes. In addition, Dox-induced cardiomyopathy models of ER-phagy reporter mice showed marked activation of ER-phagy in the myocardium compared to those of saline-treated mice. Quantitative polymerase chain reaction analyses revealed that Dox enhanced the expression of cell-cycle progression gene 1 (CCPG1), one of the ER-phagy receptors, in H9c2 cells. Ablation of CCPG1 in H9c2 cells resulted in the reduced ER-phagy activity, accumulation of proapoptotic proteins, and deterioration of cell survival against Dox administration. CCPG1-hypomorphic mice developed more severe deterioration in systolic function in response to Dox compared to wild-type mice. Conclusions: Our findings highlight a compensatory role of CCPG1-driven ER-phagy in reducing Dox toxicity. With further study, ER-phagy may be a potential therapeutic target to mitigate Dox-induced cardiomyopathy.
Nakagama et al. (Tue,) conducted a other in Anthracycline-induced cardiotoxicity. Doxorubicin vs. Saline was evaluated on ER-phagy activation and systolic function. CCPG1-driven ER-phagy was activated by doxorubicin, and its ablation in preclinical models exacerbated doxorubicin-induced apoptosis and systolic dysfunction.