Mechanism of ferroptosis in hypoxia-induced pulmonary vascular remodeling in hypoxia pulmonary hypertension: a study based on the ACE2-Ang-(1–7)-Mas axis

Abstract

Hypoxic pulmonary hypertension (HPH) is a chronic, progressive pulmonary vascular disease caused by prolonged exposure to low-oxygen conditions. Pulmonary vascular remodeling (PVR) is a key pathological feature of pulmonary artery hypertension (PAH), primarily driven by suppressed cell death and excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). Current therapies for HPH primarily focus on vasodilation rather than directly targeting PVR, highlighting the need for treatments capable of reversing VR. Ferroptosis, a recently identified form of regulated cell death, has gained attention for its potential to eliminate cancer cells; however, its involvement in PVR remains unclear. We aimed to explore whether induction of ferroptosis could suppress abnormal PASMC proliferation and mitigate hypoxia-induced PVR. In the pulmonary artery, angiotensin-converting enzyme 2 (ACE2) promotes vasodilation and inhibits PASMC proliferation, suggesting a potential therapeutic target. This study demonstrated that the expression levels of ferroptosis-related proteins-glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11)- were significantly upregulated in lung tissues and PASMCs from hypoxia-induced Sugen5416/hypoxia (SuHx) mouse models, suggesting the presence of ferroptosis resistance. Notably, ACE2 activation induced ferroptosis, whereas reduced ACE2 activity led to resistance to ferroptosis. These findings suggest that enhanced ACE2 activity may inhibit abnormal PASMC proliferation and reverse hypoxia-induced PVR, as demonstrated by both in vivo and in vitro experiments. We hypothesize that modulation of ACE2 activity influences PVR through ferroptosis regulation. This study identifies potential therapeutic targets and new research directions for the pathogenesis and treatment of HPH.