RARRES2 Knockdown Attenuates the Partial Macrophage‐Like Phenotype and Dysfunction of Vascular Smooth Muscle Cells in an In Vitro Atherosclerosis Model via the NF ‐

ABSTRACT

In atherosclerosis (AS), the conversion of vascular smooth muscle cells (VSMCs) to a macrophage‐like phenotype is a key contributor to plaque instability. Although retinoic acid receptor responder 2 (RARRES2) has been identified as an adipokine implicated in inflammation and metabolism, its role in VSMC phenotypic transformation remains unknown. This study aimed to investigate whether RARRES2 regulates the macrophage‐like transformation and dysfunction of VSMCs. In the in vitro AS model, RARRES2 expression was significantly upregulated. Knockdown of RARRES2 inhibited VSMC proliferation and migration, reduced the secretion of inflammatory factors, decreased lipid accumulation, and the number of CD68‐positive cells, and suppressed the activation of key proteins in the NF‐κB/NLRP3 pathway. In the AS model, RARRES2 expression was found to be significantly upregulated. Knockdown of RARRES2 inhibited the proliferation and migration of VSMCs, reduced the secretion of TNF‐α, IL‐6, IL‐1β, and MMP‐2, reduced lipid accumulation, decreased the number of CD68‐positive cells (indicating an acquisition of partial macrophage‐like features, though further lineage markers are needed to confirm full partial macrophage‐like phenotype), and inhibited the activation of key proteins (p‐p65, NLRP3, ASC) in the NF‐κB/NLRP3 pathway. RARRES2 knockdown suppresses NF‐κB/NLRP3 signaling and attenuates macrophage‐like transformation, inflammatory responses, and lipid accumulation in VSMCs, suggesting that RARRES2 may represent a potential therapeutic target for AS.