The mechanism of the imbalance between proliferation and ferroptosis in pulmonary artery smooth muscle cells based on the activation of SLC7A11

Abstract

Pulmonary arterial hypertension (PAH) is a chronic, progressive pulmonary vascular disease. Pulmonary vascular remodelling (PVR) is one of the main pathological features of PAH. The main cause of PVR is cell death inhibition and excessive proliferation in pulmonary artery smooth muscle cells (PASMCs), which are also affected by oxidative stress. Ferroptosis is a newly identified form of cell death, which is associated with oxidative damage. It depends on the excessive accumulation of lipid peroxides and reactive oxygen species (ROS) in cells. Solute carrier family 7 member 11 (SLC7A11) is a subunit of the cystine/glutamate antiporter system Xc^-, which inhibits ferroptosis by eliminating ROS through the promotion of GSH synthesis in cancer cells. However, very few studies exist on the relationship between ferroptosis and SLC7A11 in PAH. In this study, SLC7A11 was up-regulated in Sugen5416/hypoxia-induced PAH rats and patients with PAH. Moreover, SLC7A11 inhibited ferroptosis and promoted proliferation by overexpressing SLC7A11 in PASMCs. Additionally, ubiquitin aldehyde binding 1 (OTUB1), the main regulator of SLC7A11 stability, was involved in the ferroptosis and proliferation of PASMCs. Furthermore, erastin induced ferroptosis by inhibiting SLC7A11 and glutathione peroxidase 4 (GPX4) expressions in vivo and in vitro, suggesting that the continuous proliferation in hypoxic PASMCs could be reversed by erastin. Therefore, this study identifies novel targets and new research directions regarding PAH pathogenesis and treatment.

Keywords: Ferroptosis; Pulmonary arterial hypertension; Pulmonary artery smooth muscle cells; SLC7A11.