Smooth muscle cell-specific knockout of interferon gamma (IFN-γ) receptor attenuates intimal hyperplasia via STAT1-KLF4 activation

Lu He; Kun Gao; Hongxia Liu; Jing Wang; Xinwei Li; Chaoyong He

doi:10.1016/j.lfs.2021.119651

Smooth muscle cell-specific knockout of interferon gamma (IFN-γ) receptor attenuates intimal hyperplasia via STAT1-KLF4 activation

Life Sci. 2021 May 25:119651. doi: 10.1016/j.lfs.2021.119651. Online ahead of print.

Authors

Lu He¹, Kun Gao¹, Hongxia Liu¹, Jing Wang¹, Xinwei Li¹, Chaoyong He²

Affiliations

¹ State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China.
² State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China. Electronic address: chaoyonghecpu@126.com.

PMID: 34048810
DOI: 10.1016/j.lfs.2021.119651

Abstract

Background: Intimal hyperplasia is a main contributor to in-stent restenosis. Previous researches have shown that interferon-gamma (IFN-γ), a pleiotropic pro-inflammatory factor, plays a pathological role in intimal hyperplasia. However, the specific role and molecular mechanism of vascular smooth muscle cells (VSMCs)-derived IFN-γ receptor in intimal hyperplasia remains unknown.

Methods: We examined the distribution of IFN-γ receptor in human restenosis arteries. Then, the role of IFN-γ receptor in intimal hyperplasia was detected using VSMC-specific IFN-γ receptor-knock out carotid ligation injury models. We performed immunostaining, transwell assay and EdU staining to identify the role of IFN-γ in VSMCs proliferation and migration. The effect of IFN-γ on VSMCs phenotype switching was also investigated. Finally, we evaluated whether the mechanism of IFN-γ on intimal hyperplasia is STAT1-KLF4 dependent.

Results: The distribution of IFN-γ receptor in human restenosis arteries with VSMC-rich neointima is eventually upregulated. Specific deletion of IFN-γ receptor exhibits thinner intima and lesser proliferating VSMCs. In vitro, treatment with IFN-γ promotes human aortic VSMC (HAVSMCs) proliferation and migration, whereas specifically knock out IFN-γ receptor results in the opposite effect. Deficiency of IFN-γ receptor regulates VSMCs phenotypic switching, such as upregulated contractile markers and downregulated proliferation markers. Mechanistic studies suggest that ablation of IFN-γ receptor prevents VSMCs proliferation, migration and dedifferentiation via STAT1-KLF4 activation.

Conclusion: These results reveal that knockout of VSMC-derived IFN-γ receptor potentiates neointimal hyperplasia by preventing VSMCs proliferation, migration and dedifferentiation. Our finding implies that targeting IFN-γ-STAT1-KLF4 signaling could provide a new therapeutic strategy to attenuate vessel restenosis.

Keywords: IFN-γ receptor; Intimal hyperplasia; KLF4; Phenotypic switching; STAT1; Vessel restenosis.