CIAPIN1 functions as a redox-sensitive transcriptional repressor of Tp53 during vascular remodeling

Phenotypic switching in vascular smooth muscle cells (VSMCs) is a major driver of pathological vascular remodeling, including atherosclerosis and restenosis. Although p53 is a key regulator of VSMC homeostasis, the precise molecular mechanisms responsible for suppressing p53 expression during growth factor-induced phenotypic transitions remain incompletely understood. The present study identifies cytokine-induced apoptosis inhibitor 1 (CIAPIN1) as a novel redox-sensitive regulator of the p53 signaling axis.

Primary cultured VSMCs and a rat carotid balloon injury model were used to investigate the role of CIAPIN1 in VSMC dynamics. CIAPIN1 expression was modulated using both gain- and loss-of-function approaches. The interaction between CIAPIN1 and the Tp53 promoter was examined by dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays. Redox-dependent subcellular trafficking of CIAPIN1 was assessed using N-acetylcysteine (NAC), Ivermectin (IVM) and site-directed mutagenesis of the nuclear localization signal (NLS).

In human atherosclerotic lesions, CIAPIN1 expression was markedly upregulated, whereas Tp53 mRNA levels were significantly lower compared with healthy controls. Stimulation with PDGF-BB increased CIAPIN1 expression and the induced CIAPIN1 protein directly bound to specific consensus sites in the Tp53 promoter, thereby repressing its transcription. This CIAPIN1-mediated suppression of p53 promoted a switch toward the synthetic phenotype in VSMCs, accelerating proliferation and migration. These effects were substantially attenuated by CIAPIN1 knockdown or by restoring p53 expression. Mechanistically, PDGF-BB triggered reactive oxygen species (ROS) production, which promoted the nuclear translocation of CIAPIN1 through a functional C-terminal NLS (residues 236-239) via the classical importin-α/β pathway. Blocking this trafficking axis with the ROS scavenger NAC, the importin inhibitor IVM or genetic deletion of the NLS (∆236-239) restored p53 expression and significantly reduced neointimal formation in vivo.

CIAPIN1 functions as a redox-sensitive transcriptional repressor of Tp53, driving VSMC phenotypic switching and neointimal hyperplasia. These findings highlight CIAPIN1 as a promising and specific therapeutic target for the treatment of proliferative vascular disorders.