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Atorvastatin Inhibits Ferroptosis of H9C2 Cells by regulatingSMAD7/Hepcidin Expression to Improve
You Peng1,2,3, Bin Liao2, Yan Zhou2
1Department of Geriatric Cardiology & Guangxi Key Laboratory of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention & Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
Insights
Atorvastatin (ATV) protects against ischemia-reperfusion (I/R) cardiomyopathy by inhibiting ferroptosis. ATV improves cell viability and mitochondrial function via the SMAD7/hepcidin pathway, offering a potential therapeutic strategy for I/R injury.
Area of Science:
- Cardiovascular Biology
- Cellular Pathology
- Pharmacology
Background:
- Ferroptosis is a critical mechanism in the pathogenesis of cardiomyopathy.
- Atorvastatin (ATV) demonstrates protective effects against ischemia-reperfusion (I/R) induced cardiomyopathy.
Purpose of the Study:
- To elucidate the underlying mechanism by which Atorvastatin (ATV) exerts its protective effects in ischemia-reperfusion (I/R) injury.
Main Methods:
- Established in vitro (H9C2 cells) and in vivo (cardiomyopathy rats) models of hypoxia/reoxygenation (H/R) and I/R injury.
- Assessed cell viability (CCK8), cardiac histopathology (HE staining), mitochondrial morphology (TEM), reactive oxygen species (ROS), iron levels, and gene/protein expression (qPCR, Western blot).
Main Results:
- ATV treatment reversed H/R-induced decreases in H9C2 cell viability and mitochondrial integrity, while reducing ROS levels.
- ATV normalized iron metabolism and SMAD7/hepcidin pathway dysregulation in H/R cells and I/R rat myocardium.
- SMAD7 knockdown abrogated ATV's protective effects, confirming the pathway's importance.
Conclusions:
- Atorvastatin (ATV) mitigates ferroptosis in ischemia-reperfusion (I/R) cardiomyopathy.
- The protective mechanism involves the modulation of the SMAD7/hepcidin pathway, improving cell viability and mitochondrial function.
Background:
Ferroptosis plays a key role in cardiomyopathy. Atorvastatin (ATV) has a protective effect on ischemia-reperfusion (I/R) cardiomyopathy. The purpose of this study is to elucidate the mechanism of ATV in I/R injury.
Methods:
H9C2 cells and cardiomyopathy rats were induced by hypoxia/reoxygenation (H/R) and I/R to construct in vitro and in vivo models. Cell viability was determined by CCK8. Cardiac histopathology was observed by HE staining. Transmission electron microscope (TEM) was used to observe the mitochondrial morphology. The reactive oxygen species (ROS) content in cells was analyzed by the biochemical method. ELISA was conducted to calculate the concentrations of total iron/Fe2+ and hepcidin. The expression of ferroptosis and SMAD pathway-related genes were detected by qPCR. Western blot was performed to detect the expression levels of ferroptosis and SMAD pathway-related proteins.
Results:
In H9C2 cells, ATV reversed the decline in cell viability, mitochondrial shrinkage, and ROS elevation induced by erastin or H/R. The concentration of total iron and Fe2+ in H/R-induced H9C2 cells increased, and the protein expression of FPN1 decreased. After ATV treatment, the concentration of total iron and Fe2+ decreased, and the protein expression of FPN1 increased. The expression of the SMAD7 gene in H/R-induced H9C2 cells decreased, and the expression of the hepcidin gene increased, which were reversed by ATV. When SMAD7 was knocked down, ATV treatment failed to produce the above effect. ATV also improved ferroptosis in I/R rat myocardium through the SMAD7/hepcidin pathway.
Conclusions:
ATV reversed the decline in H9C2 cell viability, mitochondrial shrinkage, and ROS elevation, and improved the myocardium ferroptosis through the SMAD7/hepcidin pathway in I/R rat.
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