Free fatty acids stabilize integrin β1 via S-nitrosylation to promote monocyte-endothelial adhesion

Hyperlipidemia characterized by high blood levels of free fatty acids (FFA) is important for the progression of inflammatory cardiovascular diseases. Integrin β₁ is a transmembrane receptor that drives various cellular functions, including differentiation, migration, and phagocytosis. However, the underlying mechanisms modifying Integrin β₁ protein and activity in mediating monocyte/macrophage adhesion to endothelium remain poorly understood. In this study, we demonstrated that Integrin β₁ protein underwent S-nitrosylation in response to nitrosative stress in macrophages. To examine the effect of elevated levels of FFA on the modulation of Integrin β₁ expression, we treated the macrophages with a combination of oleic acid and palmitic acid (2:1) and found that FFA activated inducible nitric oxide synthase (iNOS)/nitric oxide (NO) and increased the Integrin β₁ protein level without altering the mRNA level. FFA promoted Integrin β₁ S-nitrosylation via iNOS/NO and prevented its degradation by decreasing binding to E3 ubiquitin Ligase c-Cbl. Furthermore, we found that increased Integrin α₄β₁ heterodimerization resulted in monocyte/macrophage adhesion to endothelium. In conclusion, these results provided novel evidence that FFA-stimulated NO stabilizes Integrin β₁ via S-nitrosylation, favoring Integrin α₄β₁ ligation to promote vascular inflammation.

Nitric oxide; S-nitrosylation; endothelial cell; integrin; macrophage.