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HSF1 functions as a key defender against palmitic acid-induced ferroptosis in cardiomyocytes
Nian Wang1, Heng Ma2, Jing Li2
1Department of Pathophysiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410008, China; Key Laboratory of Sepsis Translational Medicine of Hunan, Central South University, Changsha, Hunan 410008, China; Research Center of China-Africa Infectious Diseases, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410008, China.
Insights
Palmitic acid induces heart cell death via ferroptosis. Heat shock factor 1 (HSF1) protects heart cells by regulating iron and glutathione peroxidase 4 (GPX4) expression, mitigating obesity and diabetes-related cardiomyopathy.
Area of Science:
- Cardiovascular Biology
- Metabolic Disease Mechanisms
- Cell Death Pathways
Background:
- Palmitic acid (PA) contributes to cardiomyopathy in obesity and type 2 diabetes mellitus (T2DM).
- The precise mechanisms of PA-induced myocardial injury remain unclear.
- Ferroptosis, a regulated cell death pathway, is implicated in various cardiovascular conditions.
Purpose of the Study:
- To elucidate the role of heat shock factor 1 (HSF1) in palmitic acid (PA)-induced ferroptosis in cardiomyocytes.
- To investigate the molecular mechanisms by which HSF1 protects against PA-induced myocardial injury.
- To explore the therapeutic potential of targeting HSF1 in T2DM-related cardiomyopathy.
Main Methods:
- In vitro studies using H9c2 cardiomyoblasts and primary neonatal rat cardiomyocytes exposed to PA.
- Assessment of cell viability, lipid peroxidation, and iron homeostasis.
- Manipulation of HSF1 and glutathione peroxidase 4 (GPX4) expression via overexpression and knockdown.
- In vivo studies using Hsf1 knockout and wild-type mice challenged with PA.
- Analysis of gene and protein expression related to ferroptosis, iron metabolism, and endoplasmic reticulum (ER) stress.
Main Results:
- PA induced dose- and time-dependent cell death in cardiomyocytes, which was attenuated by ferroptosis inhibitors.
- PA decreased HSF1 and GPX4 protein levels, while HSF1 overexpression restored cell viability and iron homeostasis.
- HSF1 regulated iron metabolism genes and restored GPX4 expression, partly via inhibiting ER stress.
- GPX4 overexpression protected against PA-induced ferroptosis, and HSF1's protective effect was dependent on GPX4.
- Hsf1 knockout mice showed exacerbated ferroptosis and ER stress in the heart upon PA challenge.
Conclusions:
- HSF1 acts as a crucial protective factor against PA-induced ferroptosis in cardiomyocytes.
- HSF1 maintains cellular iron homeostasis and GPX4 expression, thereby preventing ferroptosis.
- Targeting HSF1 may offer a novel therapeutic strategy for managing obesity and T2DM-related cardiomyopathy.
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 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.
