Ferroptosis is essential for diabetic cardiomyopathy and is prevented by sulforaphane via AMPK/NRF2 pathways.
10.1016/j.apsb.2021.10.005
- Author:
Xiang WANG
1
;
Xinxin CHEN
2
;
Wenqian ZHOU
1
;
Hongbo MEN
1
;
Terigen BAO
1
;
Yike SUN
1
;
Quanwei WANG
3
;
Yi TAN
1
;
Bradley B KELLER
4
;
Qian TONG
3
;
Yang ZHENG
3
;
Lu CAI
1
Author Information
1. Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY 40202, USA.
2. Department of Burn Surgery, First Hospital of Jilin University, Jilin University, Changchun 130021, China.
3. Department of Cardiovascular Disease, the First Hospital of Jilin University, Changchun 130021, China.
4. Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
- Publication Type:Journal Article
- Keywords:
AMPK;
Advanced glycation end-products;
Cell death;
Diabetic cardiomyopathy;
Engineered cardiac tissue;
Ferroptosis;
Lipid peroxidation;
NRF2
- From:
Acta Pharmaceutica Sinica B
2022;12(2):708-722
- CountryChina
- Language:English
-
Abstract:
Herein, we define the role of ferroptosis in the pathogenesis of diabetic cardiomyopathy (DCM) by examining the expression of key regulators of ferroptosis in mice with DCM and a new ex vivo DCM model. Advanced glycation end-products (AGEs), an important pathogenic factor of DCM, were found to induce ferroptosis in engineered cardiac tissues (ECTs), as reflected through increased levels of Ptgs2 and lipid peroxides and decreased ferritin and SLC7A11 levels. Typical morphological changes of ferroptosis in cardiomyocytes were observed using transmission electron microscopy. Inhibition of ferroptosis with ferrostatin-1 and deferoxamine prevented AGE-induced ECT remodeling and dysfunction. Ferroptosis was also evidenced in the heart of type 2 diabetic mice with DCM. Inhibition of ferroptosis by liproxstatin-1 prevented the development of diastolic dysfunction at 3 months after the onset of diabetes. Nuclear factor erythroid 2-related factor 2 (NRF2) activated by sulforaphane inhibited cardiac cell ferroptosis in both AGE-treated ECTs and hearts of DCM mice by upregulating ferritin and SLC7A11 levels. The protective effect of sulforaphane on ferroptosis was AMP-activated protein kinase (AMPK)-dependent. These findings suggest that ferroptosis plays an essential role in the pathogenesis of DCM; sulforaphane prevents ferroptosis and associated pathogenesis via AMPK-mediated NRF2 activation. This suggests a feasible therapeutic approach with sulforaphane to clinically prevent ferroptosis and DCM.
