Department of Cerebrovascular Diseases, the Second Affiliated Hospital of Kunming Medical University, Kunming, China.
Department of Neurosurgery, the Second Affiliated Hospital of Kunming Medical University, Kunming, China.
J Biochem Mol Toxicol. 2024 Dec;38(12):e70066. doi: 10.1002/jbt.70066.
Atherosclerosis (AS) is a chronic multifactorial disease with damage to vascular endothelial cells (VECs). This study sought to delve into the mechanism of methyltransferase-like 14 (METTL14) in iron overload-induced lipid peroxidative damage in AS. AS mouse model and cell model were established. Levels of METTL14/circRNA coded by the Arhgap12 (circARHGAP12)/Aspartate β-hydroxylase (ASPH) were determined. AS plaque area/lipid deposition/lipid metabolism in AS mice and iron overload in VECs were evaluated. N6-methyladenosine (m6A) level and METTL14 enrichment and human antigen R (HuR) in circARHGAP12 or ASPH were measured. The mRNA stability of circARHGAP12 or ASPH was analyzed. We observed that METTL14 was upregulated in AS mice. METTL14 downregulation reduced plaque area/lipid deposition/iron overload/peroxidative damage in AS mice. In cell models, METTL14 downregulation could VEC injury/iron overload/lipid peroxidative damage. Mechanically, METTL14 increased the stability and expression of circARHGAP12 through m6A modification, further stabilized ASPH mRNA, and promoted ASPH transcription by binding to HuR. Overexpression of circARHGAP12 or inhibition of ASPH averted the protective role of METTL14 downregulation against iron overload-induced peroxidative damage in AS. In conclusion, METTL14-mediated m6A modification upregulated circARHGAP12 and ASPH to aggravate overload-induced lipid peroxidative damage and facilitate AS progression.
动脉粥样硬化（AS）是一种慢性多因素疾病，会损伤血管内皮细胞（VECs）。本研究旨在深入探讨甲基转移酶样 14（METTL14）在 AS 中铁过载诱导的脂质过氧化损伤中的作用机制。建立了 AS 小鼠模型和细胞模型。测定 METTL14/由 Arhgap12（circARHGAP12）/天冬氨酸β-羟化酶（ASPH）编码的环状 RNA（circRNA）水平。评估 AS 小鼠 AS 斑块面积/脂质沉积/脂质代谢和 VEC 中铁过载情况。测量 N6-甲基腺苷（m6A）水平和 METTL14 富集以及 circARHGAP12 或 ASPH 中的 HuR。分析 circARHGAP12 或 ASPH 的 mRNA 稳定性。结果显示，AS 小鼠中 METTL14 上调。METTL14 下调可减少 AS 小鼠的斑块面积/脂质沉积/铁过载/过氧化损伤。在细胞模型中，METTL14 下调可减轻 VEC 损伤/铁过载/脂质过氧化损伤。机制上，METTL14 通过 m6A 修饰增加 circARHGAP12 的稳定性和表达，进一步稳定 ASPH mRNA，并通过与 HuR 结合促进 ASPH 转录。circARHGAP12 的过表达或 ASPH 的抑制可逆转 METTL14 下调对 AS 中铁过载诱导的过氧化损伤的保护作用。综上所述，METTL14 介导的 m6A 修饰上调 circARHGAP12 和 ASPH，加重铁过载诱导的脂质过氧化损伤，促进 AS 进展。
