PCSK6 attenuates cardiac dysfunction in doxorubicin-induced cardiotoxicity by regulating autophagy

Doxorubicin (DOX) is a chemotherapeutic drug widely used in the field of cancer, but its side effects on the heart hinder its clinical application. In cardiac injury caused by DOX, apoptosis and oxidative stress are both involved in cardiac damage, and autophagy is also one of the key responses. Both apoptosis and oxidative stress interact with autophagy. Proper promotion of autophagy effectively protects the myocardium and blocks cardiac injury. DOX mainly acts downstream of the autophagic flow and hinders the degradation process of autophagolysosomes, resulting in abnormal accumulation of autophagolysosomes in cells, which can prevent the timely removal of harmful substances and disrupt the normal function of cells. Proprotein convertase subtilisin/kexin type 6 (PCSK6) is involved in the occurrence and development of various cardiovascular diseases, blood pressure regulation and the inflammatory response, but its role in DOX is still unclear. Here, we constructed cardiac PCSK6-overexpressing mice by injecting AAV9-PCSK6. Both in vivo and in vitro experiments confirmed that overexpression of PCSK6 effectively protected cardiac function, inhibited apoptosis and oxidative stress. We focused on the effect of PCSK6 overexpression on autophagy. We have detected an increase in autophagosomes production and a decrease in autophagolysosomes accumulation. This suggests that PCSK6 promotes the level of autophagy, while possibly acting on the sites where DOX inhibits degradation, so that the autophagic flux inhibited by DOX is restored and the degradation process of autophagolysosomes is restored. The effect of PCSK6 was dependent on FOXO3a, which promoted the nuclear translocation of Forkhead box O3 (FOXO3a), and Sirtuin 1 (SIRT1) regulated the expression of FOXO3a. When SIRT1 was inhibited, the protective effect of PCSK6 was diminished. In conclusion, overexpression of PCSK6 exerts a protective effect through SIRT1/FOXO3a in cardiac injury induced by DOX, suggesting that PCSK6 may be a therapeutic target for DOX cardiomyopathy.