ZHX2 alleviates vascular remodeling and smooth muscle cell proliferation by transcriptional regulation of GADD45G

Abstract

ObjectiveThis study explores the role of ZHX2 in vascular remodeling, specifically focusing on its effects on VSMC proliferation, migration, and neointima formation following vascular injury. Methods and Results: Data from both human atherosclerotic samples and a mouse carotid injury model indicated a decrease in ZHX2 levels. In vivo, ZHX2 overexpression reduced neointima formation in mice subjected to carotid artery ligation. In vitro, ZHX2 inhibited the proliferation and migration of primary VSMCs. Conversely, specific knockout of ZHX2 in SMCs in vivo or knockdown of ZHX2 in primary VSMCs had opposite effects. RNA- seq analysis revealed that ZHX2 overexpression significantly affected the expression of cell cycle-related genes. Using Chromatin Immunoprecipitation Sequencing (ChIP-seq) and luciferase reporter assays, we demonstrated that ZHX2 plays a crucial role in the transcriptional regulation of GADD45G, identifying GADD45G as the downstream target responsible for ZHX2-mediated effects. Conclusions: ZHX2 emerges as a key player in pathological vascular remodeling, suppressing VSMC proliferation and migration through its regulatory impact on GADD45G transcription and cell cycle-related gene expression.