Methylseleninic Acid Elevating the Nrf2-GPX4 Axis Relieves Endothelial Dysfunction and Ferroptosis Induced by Arsenic Exposure

Chronic exposure to arsenic (As), a ubiquitous contaminant, poses deleterious health risks to humans, including cardiovascular disease. Recent studies have implicated ferroptosis, in which the essential micronutrient selenium (Se) plays a crucial role, in several As-induced pathological processes. However, whether Se can counteract As-induced endothelial dysfunction through ferroptosis remains unclear. Herein, methylseleninic acid (MSA), a methylselenium metabolite, was used as a Se supplement to investigate the underlying effect and mechanism of Se in As-induced endothelial dysfunction involving ferroptosis in vivo and in vitro. As exposure induced endothelial dysfunction in mice, as indicated by increased aortic permeability, increased number of circulating endothelial cells, and endothelial mitochondria exhibiting ferroptosis-related alterations. Additionally, As induced ferroptosis-related cell death in mouse aortic endothelial cells, accompanied by impaired redox homeostasis, relatively low Se status, and decreased expressions of selenoproteome, including GPX4. Notably, these were attenuated by MSA via activation of Nrf2 and upregulation of three GPX4 isoforms, which were further abrogated by the Nrf2 antagonist ML385. Finally, MSA exhibited ameliorative effects on endothelial ferroptosis and dysfunction in the aortas of As-exposed mice. These results demonstrate that As causes endothelial ferroptosis and dysfunction by affecting the Se-Nrf2/GPX4 axis, which can be relieved by MSA. This study provides novel evidence implicating Se in As-induced endothelial dysfunction by mitigating ferroptosis.