Exogenous spermidine alleviates diabetic cardiomyopathy via suppressing Pannexin-1-mediated ferroptosis in db/db mice

Diabetic cardiomyopathy (DCM) is a serious complication and death cause of diabetes mellitus (DM). Recent cardiology studies suggest that spermidine has cardioprotective effects. Here, the hypothesis was tested the spermidine effects of DCM. Therefore, db/db mice and primary neonatal mouse cardiomyocytes were used to observe the effects of spermidine. Immunoblotting showed that ornithine decarboxylase (ODC) and SPD/spermine N1-acetyltransferase (SSAT) were downregulated and upregulated in the myocardium of db/db mice, respectively. We found that diabetic mice showed cardiac dysfunction in 12 weeks. Conversely, exogenous spermidine could improve cardiac functions and reduce the deposition of collagens, myocardial damage, ROS levels and endoplasmic reticulum stress in diabetic mouse hearts. Our results also demonstrated that cardiomyocytes appeared ferroptosis and then activated Pannexin-1 expression, which resulted in increasing the extracellular ATP. Subsequently, increased ATP as a paracrine molecule combined to P2X7 receptors to activate ERK1/2 signaling pathway in cardiomyocytes, and activated NCOA4-mediated ferroptinophagy to promote lipid peroxidation and ferroptosis. Interestingly, spermidine could reverse these molecular processes. Our findings indicate an important new mechanism for DCM, and suggest spermidine have potential applicability to protect against deterioration of cardiac function with DCM.