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 was significant after carotid ligation for 4 wk in ApoE-/- mice. IFN-γ mAb, T0, and 4-PBA treatment not only significantly attenuated neointimal hyperplasia but also decreased CD68+ TUNEL+ double-positive macrophages in the hyperplastic neointima. Moreover, after 4-PBA or T0 administration, the number of CD68+ p-eIIF2α+ and CD68+ CHOP+ double-positive cells in neointimal was also apparently decreased. Taken together, these results defined an unexpected role of IFN-γ and LXR-α in the development of neointimal hyperplasia. The PIAS1/STAT1-dependent LXR-α degradation induced by IFN-γ promoted ER stress and apoptosis in macrophages, which leads to aggravated neointimal hyperplasia. LXR agonist efficiently improved neointimal hyperplasia, which may be a promising new strategy to ameliorate restenosis and vascular remodeling after PCI.-Zhao, Q., Zhou, D., You, H., Lou, B., Zhang, Y., Tian, Y., Guo, N., Chen, X., Liu, Y., Wu, Y., Yuan, Z., Zhou, J. IFN-γ aggravates neointimal hyperplasia by inducing endoplasmic reticulum stress and apoptosis in macrophages by promoting ubiquitin-dependent liver X receptor-α degradation.