ZFP36L2 Promotes Aortic Dissection by Targeting KCNJ15 mRNA Degradation to Suppress AKT2/3 Signaling in Smooth Muscle Cells

ABSTRACT: Aortic dissection (AD) is a life-threatening vascular disease lacking effective pharmacotherapy. Phenotypic switching of vascular smooth muscle cells (VSMCs) from contractile to synthetic state drives medial degeneration, but the upstream post-transcriptional regulators remain elusive. This study investigates the role of the RNA-binding protein ZFP36L2 in VSMC phenotypic switching during AD. Single-cell RNA sequencing (GSE222318) was analyzed to map ZFP36L2 dynamics along the VSMC pseudotime trajectory. Human AD aortic tissues and a beta-aminopropionitrile (BAPN)-induced mouse model were used for validation. VSMC-specific ZFP36L2 knockdown was achieved via AAV9-EnSM22alpha-shZFP36L2. Mechanistic studies included RNA immunoprecipitation, RNA pull-down, mRNA stability assays, dual-luciferase reporter assays, membrane potential measurements, and AKT isoform-specific phosphorylation analysis. ZFP36L2 expression progressively increased along the pseudotime trajectory from contractile to synthetic/lipo-VSMCs and was significantly upregulated in human AD tissues and BAPN-treated mouse aortas. VSMC-specific ZFP36L2 silencing improved survival, reduced aortic dilation, and preserved medial integrity in BAPN-treated mice. Mechanistically, ZFP36L2 directly bound the AU-rich element within the 3'UTR of KCNJ15 mRNA via its zinc finger domain (C174), promoting mRNA degradation. Reduced KCNJ15 led to decreased K+ efflux, membrane depolarization, and selective inhibition of AKT2 and AKT3 phosphorylation (but not AKT1), driving VSMCs toward a synthetic phenotype. Rescue experiments confirmed KCNJ15 is necessary and sufficient for ZFP36L2-mediated effects, and the AKT inhibitor MK-2206 abolished KCNJ15's protective action. ZFP36L2 drives VSMC phenotypic switching in AD through the KCNJ15-AKT2/3 axis, revealing a novel post-transcriptional regulatory mechanism and a potential therapeutic target for AD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE343724 | GEO | 2026/08/18

REPOSITORIES: GEO