Exogenous spermidine alleviates diabetic cardiomyopathy via suppressing reactive oxygen species, endoplasmic reticulum stress, and Pannexin-1-mediated ferroptosis

Jian Sun; Jiyu Xu; Yong Liu; Yitong Lin; Fengge Wang; Yue Han; Shumin Zhang; Xiaoyan Gao; Changqing Xu; Hui Yuan

doi:10.17305/bb.2022.8846

Authors

Jian Sun School of Basic Medical Sciences, Mudanjiang Medical University, Mudanjiang, China https://orcid.org/0000-0003-3419-0722
Jiyu Xu School of Medical Imaging, Mudanjiang Medical University, Mudanjiang, China https://orcid.org/0000-0001-5646-9447
Yong Liu Animal Research Institute, Research Department, Mudanjiang Medical University, Mudanjiang, China https://orcid.org/0000-0002-6999-4272
Yitong Lin School of Basic Medical Sciences, Mudanjiang Medical University, Mudanjiang, China https://orcid.org/0009-0009-9424-5802
Fengge Wang The Fifth Affiliated Hospital of Southern Medical University, Guangzhou, China https://orcid.org/0009-0008-7728-2751
Yue Han School of Basic Medical Sciences, Mudanjiang Medical University, Mudanjiang, China https://orcid.org/0009-0006-1532-3824
Shumin Zhang School of Stomatology, Mudanjiang Medical University, Mudanjiang, China https://orcid.org/0009-0001-6419-812X
Xiaoyan Gao School of Basic Medical Sciences, Mudanjiang Medical University, Mudanjiang, China https://orcid.org/0009-0002-7281-2895
Changqing Xu Department of Pathophysiology, Harbin Medical University, Harbin, China https://orcid.org/0009-0006-7731-5723
Hui Yuan School of Basic Medical Sciences, Mudanjiang Medical University, Mudanjiang, China; School of Stomatology, Mudanjiang Medical University, Mudanjiang, China https://orcid.org/0000-0001-5646-9447

DOI:

https://doi.org/10.17305/bb.2022.8846

Keywords:

Diabetic cardiomyopathy, Spermidine, ferroptosis, Pannexin-1, P2X7

Abstract

Diabetic cardiomyopathy (DCM) is a serious complication and death cause of diabetes mellitus (DM). Recent cardiology studies suggest that spermidine (SPD) has cardioprotective effects. Here, we verified the hypothesis of SPD’s protective effects on DCM. Therefore, db/db mice and primary neonatal mouse cardiomyocytes were used to observe the effects of SPD. 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 SPD could improve cardiac functions and reduce the deposition of collagens, myocardial damage, reactive oxygen species (ROS) levels, and endoplasmic reticulum stress (ERS) in diabetic mouse hearts. Our results also demonstrated that cardiomyocytes displayed ferroptosis and then activated Pannexin-1 expression, which resulted in the increase of the extracellular adenosine triphosphate (ATP). Subsequently, increased ATP as a paracrine molecule combined to purinergic receptor P2X7 to activate ERK1/2 signaling pathway in cardiomyocytes and activated NCOA4-mediated ferroptinophagy to promote lipid peroxidation and ferroptosis. Interestingly, SPD could reverse these molecular processes. Our findings indicate an important new mechanism for DCM and suggest that SPD has potential applicability to protect against deterioration of cardiac function with DCM.