3.1.3 Ferroptosis is involved in inducing plaque progression in AS
Plaque rupture, intra-plaque bleeding, and thrombosis are also important causes of AS progression. In the process of plaque formation in the late stage of human carotid artery atherosclerosis, oxygen consumption in the blood vessel wall increases and plaque lesions undergo hypoxia, which stimulates angiogenesis and the resulting blood vessels are highly permeable and brittle66. Moreover, advanced plaques contain a large number of macrophages with pro-inflammatory phenotypes that secrete stroma-degrading enzymes, leading to plaque instability, plaque rupture, intra-plaque bleeding, and thrombotic events67.
GPX4 is an important antioxidant and plays an anti-ferroptosis role in the body. The severity of atherosclerosis was negatively correlated with GPX4 expression68. Overexpression of GPX4 inhibits the development of atherosclerosis by decreasing lipid peroxidation and inhibiting the sensitivity of vascular cells to oxidized lipids69. By up-regulating GPX4 expression and enhancing GPX4 catalytic activity, vascular smooth muscle cell proliferation can be inhibited and arterial protection can be enhanced70. A single dose of selenium delivered to the brain promotes the expression of the antioxidant GPX4, protects neurons, and inhibits plaque growth in AS71. It was found that Qing-Xin-Jie-Yu Granule partially inhibited ferroptosis in vulnerable AS plaques through GPX4/ Xc- signaling pathway and weakened AS progression72. Thus, upregulation of GPX4 expression can slow plaque progression in AS by inhibiting ferroptosis.
Long non-coding RNAs (lncRNAs) have been associated with atherosclerosis (AS), and lncRNA PVT1 was found to be significantly upregulated in serum of patients with AS. In vitro experiments using human vascular endothelial cells (HUVECs) showed that knockdown of PVT1 and miR-106b-5p overexpression inhibited increases in iron content, MDA levels, lipid ROS, ACSL4, and PTGS2, as well as decreases in GSH and GPX4 in oxygen-LDL-induced HUVECs. The study also found that PVT1 knockdown decreased lipid deposition, atherosclerotic plaque number and size in ApoE mice. These results suggest that PVT1 plays a key role in the progression of AS by regulating the miR-106b-5p/ACSL4 axis in HUVECs, and therefore may be a potential therapeutic target for AS73.