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

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.