1. HSF1 functions as a key defender against palmitic acid-induced ferroptosis in cardiomyocytes.
- Author
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Wang, Nian, Ma, Heng, Li, Jing, Meng, ChaoYang, Zou, Jiang, Wang, Hao, Liu, Ke, Liu, Meidong, Xiao, Xianzhong, Zhang, Huali, and Wang, Kangkai
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PALMITIC acid , *HEAT shock factors , *TYPE 2 diabetes , *GLUTATHIONE peroxidase , *CELL death , *PROTEIN expression - Abstract
Palmitic acid (PA)-induced myocardial injury is considered a critical contributor to the development of obesity and type 2 diabetes mellitus (T2DM)-related cardiomyopathy. However, the underlying mechanism has not been fully understood. Here, we demonstrated that PA induced the cell death of H9c2 cardiomyoblasts in a dose- and time-dependent manner, while different ferroptosis inhibitors significantly abrogated the cell death of H9c2 cardiomyoblasts and primary neonatal rat cardiomyocytes exposed to PA. Mechanistically, PA decreased the protein expression levels of both heat shock factor 1 (HSF1) and glutathione peroxidase 4 (GPX4) in a dose- and time-dependent manner, which were restored by different ferroptosis inhibitors. Overexpression of HSF1 not only alleviated PA-induced cell death and lipid peroxidation but also improved disturbed iron homeostasis by regulating the transcription of iron metabolism-related genes (e.g., Fth1 , Tfrc , Slc40a1). Additionally, PA-blocked GPX4 protein expression was evidently restored by HSF1 overexpression. Inhibition of endoplasmic reticulum (ER) stress rather than autophagy contributed to HSF1-mediated GPX4 expression. Moreover, GPX4 overexpression protected against PA-induced ferroptosis, whereas knockdown of GPX4 reversed the anti-ferroptotic effect of HSF1. Consistent with the in vitro findings, PA-challenged Hsf 1−/− mice exhibited more serious ferroptosis, increased Slc40a1 and Fth1 mRNA expression, decreased GPX4 and TFRC expression and enhanced ER stress in the heart compared with Hsf 1+/+ mice. Altogether, HSF1 may function as a key defender against PA-induced ferroptosis in cardiomyocytes by maintaining cellular iron homeostasis and GPX4 expression. Unlabelled Image • Ferroptosis is involved in PA-induced cell death in cardiomyocytes. • HSF1 protects cardiomyocytes against PA-induced ferroptosis. • GPX4 is required for the anti-ferroptotic function of HSF1 in PA-induced cardiomyocyte death. • ER stress activation contributes to HSF1-mediated GPX4 expression in PA-challenged cardiomyocytes. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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