Hcy Promotes a Pro-inflammatory and Migratory Macrophage Phenotype through the Rap1A/MAPK Signaling Pathway

Hyperhomocysteinemia (HHcy) is an important risk factor for various vascular diseases, and macrophage dysfunction plays a crucial role in the vascular injury aggravated by HHcy. However, the mechanism underlying homocysteine (Hcy)-induced macrophage dysfunction remains unclear. In this study, we established an in vitro HHcy model by treating cultured ANA-1 macrophages with Hcy, then confirmed that the biological dysfunction of ANA-1 macrophages induced by Hcy was companied by the upregulation of Rap1A. Meanwhile, Rap1A interference reversed Hcy-induced cell proliferation, migration and invasion, while also reduced macrophage inflammatory response and M1 polarization. Furthermore, after Rap1A knockdown, phosphorylation of ERK1/2 was inhibited, and ERK1/2 suppression alleviated Hcy-induced macrophage dysfunction. Collectively, our findings indicate that Rap1A mediates the pro-inflammatory and migratory phenotype of macrophages induced by Hcy through the ERK1/2 signaling pathway, thereby providing novel insights into the pathogenesis of HHcy-associated vascular diseases.