IFN-γ aggravates neointimal hyperplasia by inducing endoplasmic reticulum stress and apoptosis in macrophages by promoting ubiquitin-dependent liver X receptor-α degradation

Neointimal hyperplasia is the main cause of restenosis after percutaneous coronary interventions (PCIs). Both IFN-γ and macrophages play nonredundant roles in the pathogenesis of vascular intimal hyperplasia; however, the underlying mechanisms remain elusive and must be further investigated. In mouse peritoneal macrophages, IFN-γ significantly accelerated degradation and up-regulated polyubiquitination of liver X receptor (LXR)-α. Signal transducer and activator of transcription 1 (STAT1) inhibitor, fludarabine, and PIAS1 knockdown reduced ubiquitination and increased the expression of LXR-α in IFN-γ–treated macrophages. IFN-γ also increased the expression of endoplasmic reticulum (ER) stress–related proteins, including p-PERK, p-eIIF2α, and CCAAT-enhancer-binding protein homologous protein (CHOP), as well as apoptosis of macrophages. Treatment with ER stress inhibitor, 4-phenylbutyric acid (4-PBA), and LXR agonist, T0901317 (T0), alleviated IFN-γ–induced apoptosis in macrophages. Neointimal hyperplasia w...