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. 2023 Jun;37(3):471-486.
doi: 10.1007/s10557-022-07348-6. Epub 2022 Jun 15.

Silencing METTL3 Stabilizes Atherosclerotic Plaques by Regulating the Phenotypic Transformation of Vascular Smooth Muscle Cells via the miR-375-3p/PDK1 Axis

Jingquan Chen  1 , Kun Lai  1 , Xi Yong  1 , Hongshun Yin  1 , Zhilong Chen  1 , Haifei Wang  1 , Kai Chen  1 , Jianghua Zheng  2
Affiliations

Silencing METTL3 Stabilizes Atherosclerotic Plaques by Regulating the Phenotypic Transformation of Vascular Smooth Muscle Cells via the miR-375-3p/PDK1 Axis

Jingquan Chen et al. Cardiovasc Drugs Ther. 2023 Jun.

Abstract

Purpose: Atherosclerosis (AS) is a primary cause of cardiovascular diseases. This study investigated the mechanism of methyltransferase-like 3 (METTL3) in AS plaques via modulating the phenotypic transformation of vascular smooth muscle cells (VSMCs).

Methods: AS mouse models and MOVAS cell models were established through high-fat diet and the treatment of ox-LDL, respectively. METTL3 expression in AS models was detected via RT-qPCR and Western blot. The AS plaques, lipid deposition, and collagen fibers were examined via histological staining. The levels of Ly-6c, α-SMA, and OPN were examined via Western blot. The blood lipid indexes in mouse aortic tissues were determined using kits. The proliferation and migration of MOVAS cells were detected via CCK-8 and Transwell assays. The m6A modification level of mRNA was quantified. The binding relationship between pri-miR-375 and DGCR8, and the enrichment of m6A on pri-miR-375 were detected via RIP. The binding relationship between miR-375-3p and 3-phosphoinositide-dependent protein kinase-1 (PDK1) was verified via dual-luciferase assay. Joint experiments were designed to investigate the role of miR-375-3P/PDK1 in the phenotypic transformation of VSMCs.

Results: METTL3 was highly expressed in AS. Silencing METTL3 alleviated AS progression and stabilized AS plaques in mice, and limited the phenotypic transformation of VSMCs induced by ox-LDL. Silencing METTL3 inhibited m6A level and decreased the binding of DGCR8 to pri-miR-375 and further limited miR-375-3p expression. miR-375-3p targeted PDK1 transcription. miR-375-3p upregulation or PDK1 downregulation facilitated the phenotypic transformation of VSMCs.

Conclusion: METTL3-mediated m6A modification promoted VSMC phenotype transformation and made AS plaques more vulnerable via the miR-375-3p/PDK1 axis.

Keywords: Atherosclerotic plaque; METTL3; Phenotypic transformation of vascular smooth muscle; m6A modification; miR-375-3p; pri-miR-375.

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