Abstract
As one of the cornerstones of clinical cardiovascular disease treatment, statins have an extensive range of applications. However, statins commonly used have side reactions, especially muscle-related symptoms (SAMS), such as muscle weakness, pain, cramps, and severe condition of rhabdomyolysis. This undesirable muscular effect is one of the chief reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. Moreover, the underlying mechanism of muscle cell damage is still unclear. Here, we discovered that ferroptosis, a programmed iron-dependent cell death, serves as a mechanism in statin-induced myopathy. Among four candidates including atorvastatin, lovastatin, rosuvastatin, and pravastatin, only atorvastatin could lead to ferroptosis in human cardiomyocytes (HCM) and murine skeletal muscle cells (C2C12), instead of human umbilical vein endothelial cell (HUVEC). Atorvastatin inhibits HCM and C2C12 cell viability in a dose-dependent manner, accompanying with significant augmentation in intracellular iron ions, reactive oxygen species (ROS), and lipid peroxidation. A noteworthy investigation found that those alterations particularly occurred in mitochondria and resulted in mitochondrial dysfunction. Biomarkers of myocardial injury increase significantly during atorvastatin intervention. However, all of the aforementioned enhancement could be restrained by ferroptosis inhibitors. Mechanistically, GSH depletion and the decrease in nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPx4), and xCT cystine–glutamate antiporter (the main component is SLC7A11) are involved in atorvastatin-induced muscular cell ferroptosis and damage. The downregulation of GPx4 in mitochondria-mediated ferroptosis signaling may be the core of it. In conclusion, our findings explore an innovative underlying pathophysiological mechanism of atorvastatin-induced myopathy and highlight that targeting ferroptosis serves as a protective strategy for clinical application.
Highlights
Statins, inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, are the most extensively applied cholesterol-reducing medicine to prevent cardiovascular events (Downs et al, 1998)
In order to explore whether restriction of ferroptosis could prevent the cell damage induced by atorvastatin and lovastatin, the cells were preprocessed with deferoxamine mesylate (DFO), Fer-1 or Lip-1 for 2 h and cocultured with atorvastatin or lovastatin for another 24 h
Only cell death caused by atorvastatin can be restrained by the treatment with ferroptosis inhibitor, such as DFO (Figures 1B,F), Fer-1 (Figures 1C,G) and Lip-1 (Figures 1D,H), while cell death caused by lovastatin cannot be rescued by
Summary
Inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, are the most extensively applied cholesterol-reducing medicine to prevent cardiovascular events (Downs et al, 1998). Previous studies about SAMS focused on skeletal muscle, and the majority of mechanisms were centered on mitochondrial dysfunction, oxidative stress, immune-mediated necrotizing myopathy, and inhibition of isoprenylation of small G-proteins, owing to impaired mevalonate metabolism upon skeletal muscle damage (Cao et al, 2009; Musset et al, 2016; Thompson et al, 2016; Tiniakou and Christopher-Stine, 2017). These just account for only a small percentage of it. As for cardiac muscle, a special kind of striated muscle, previous reports demonstrated that the mechanisms of SAMS in cardiac muscle mainly concentrate on mitochondrial dysfunction and apoptosis (Bonifacio et al, 2016; Godoy et al, 2019)
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