Irisin attenuates type 1 diabetic cardiomyopathy by anti-ferroptosis via SIRT1-mediated deacetylation of p53

Yuan-Juan Tang, Department of Cardiology, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, 610031, China.
Zhen Zhang, Department of Cardiology, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, 610031, China.
Tong Yan, Department of Cardiology, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, 610031, China.
Ken Chen, Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, 400042, China.
Guo-Fan Xu, Department of Cardiology and Endocrinolgy, Pangang Group Chengdu Hospital, Chengdu, 610066, China.
Shi-Qiang Xiong, Department of Cardiology, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, 610031, China.
Dai-Qian Wu, Department of Cardiology, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, 610031, China.
Jie Chen, Department of Cardiovascular Surgery, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, 610031, China.
Pedro A. Jose, Division of Renal Diseases & Hypertension, Department of Medicine and Department of Physiology/Pharmacology, The George Washington University School of Medicine & Health Sciences, Washington, DC, 20037, USA.
Chun-Yu Zeng, Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, 400042, China. chunyuzeng01@163.com.
Jin-Juan Fu, Department of Cardiology, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, 610031, China. fujinjuan@swjtu.edu.cn.

Document Type

Journal Article

Publication Date

4-2-2024

Journal

Cardiovascular diabetology

Volume

23

Issue

1

DOI

10.1186/s12933-024-02183-5

Keywords

Ferroptosis; Irisin; SIRT1; Type 1 diabetic cardiomyopathy; p53

Abstract

BACKGROUND: Diabetic cardiomyopathy (DCM) is a serious complication in patients with type 1 diabetes mellitus (T1DM), which still lacks adequate therapy. Irisin, a cleavage peptide off fibronectin type III domain-containing 5, has been shown to preserve cardiac function in cardiac ischemia-reperfusion injury. Whether or not irisin plays a cardioprotective role in DCM is not known. METHODS AND RESULTS: T1DM was induced by multiple low-dose intraperitoneal injections of streptozotocin (STZ). Our current study showed that irisin expression/level was lower in the heart and serum of mice with STZ-induced TIDM. Irisin supplementation by intraperitoneal injection improved the impaired cardiac function in mice with DCM, which was ascribed to the inhibition of ferroptosis, because the increased ferroptosis, associated with increased cardiac malondialdehyde (MDA), decreased reduced glutathione (GSH) and protein expressions of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), was ameliorated by irisin. In the presence of erastin, a ferroptosis inducer, the irisin-mediated protective effects were blocked. Mechanistically, irisin treatment increased Sirtuin 1 (SIRT1) and decreased p53 K382 acetylation, which decreased p53 protein expression by increasing its degradation, consequently upregulated SLC7A11 and GPX4 expressions. Thus, irisin-mediated reduction in p53 decreases ferroptosis and protects cardiomyocytes against injury due to high glucose. CONCLUSION: This study demonstrated that irisin could improve cardiac function by suppressing ferroptosis in T1DM via the SIRT1-p53-SLC7A11/GPX4 pathway. Irisin may be a therapeutic approach in the management of T1DM-induced cardiomyopathy.

Department

Medicine

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