Statin-Induced Geranylgeranyl Pyrophosphate Depletion Promotes Ferroptosis-Related Senescence in Adipose Tissue.
Xin ShuJiaqi WuTao ZhangXiaoyu MaZuoqin DuJin XuJingcan YouLiqun WangNi ChenMao LuoJianbo WuPublished in: Nutrients (2022)
Statin treatment is accepted to prevent adverse cardiovascular events. However, atorvastatin, an HMG-CoA reductase inhibitor, has been reported to exhibit distinct effects on senescent phenotypes. Whether atorvastatin can induce adipose tissue senescence and the mechanisms involved are unknown. The effects of atorvastatin-induced senescence were examined in mouse adipose tissue explants. Here, we showed that statin initiated higher levels of mRNA related to cellular senescence markers and senescence-associated secretory phenotype (SASP), as well as increased accumulation of the senescence-associated β-galactosidase (SA-β-gal) stain in adipose tissues. Furthermore, we found that the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and Fe 2+ were elevated in adipose tissues treated with atorvastatin, accompanied by a decrease in the expression of glutathione (GSH), and glutathione peroxidase 4 (GPX4), indicating an iron-dependent ferroptosis. Atorvastatin-induced was prevented by a selective ferroptosis inhibitor (Fer-1). Moreover, supplementation with geranylgeranyl pyrophosphate (GGPP), a metabolic intermediate, reversed atorvastatin-induced senescence, SASP, and lipid peroxidation in adipose tissue explants. Atorvastatin depleted GGPP production, but not Fer-1. Atorvastatin was able to induce ferroptosis in adipose tissue, which was due to increased ROS and an increase in cellular senescence. Moreover, this effect could be reversed by the supplement of GGPP. Taken together, our results suggest that the induction of ferroptosis contributed to statin-induced cell senescence in adipose tissue.
Keyphrases
- adipose tissue
- dna damage
- endothelial cells
- high glucose
- cell death
- insulin resistance
- stress induced
- diabetic rats
- high fat diet
- reactive oxygen species
- coronary artery disease
- cardiovascular events
- drug induced
- oxidative stress
- metabolic syndrome
- emergency department
- single cell
- poor prognosis
- newly diagnosed
- cell proliferation
- type diabetes
- mesenchymal stem cells
- skeletal muscle
- combination therapy
- cell cycle arrest