HSF1 functions as a key defender against palmitic acid-induced ferroptosis in cardiomyocytes.

Nian Wang, Heng Ma, Jing Li, ChaoYang Meng, Jiang Zou, Hao Wang, Ke Liu, Meidong Liu, Xianzhong Xiao, Huali Zhang, Kangkai Wang

Journal of molecular and cellular cardiology 2021 Jan

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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 Hsf1-/- 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 Hsf1+/+ mice. Altogether, HSF1 may function as a key defender against PA-induced ferroptosis in cardiomyocytes by maintaining cellular iron homeostasis and GPX4 expression. Copyright © 2020 Elsevier Ltd. All rights reserved.

Citation

Nian Wang, Heng Ma, Jing Li, ChaoYang Meng, Jiang Zou, Hao Wang, Ke Liu, Meidong Liu, Xianzhong Xiao, Huali Zhang, Kangkai Wang. HSF1 functions as a key defender against palmitic acid-induced ferroptosis in cardiomyocytes. Journal of molecular and cellular cardiology. 2021 Jan;150:65-76