title: Interferon regulatory factor 8 modulates phenotypic switching of smooth muscle cells by regulating the activity of myocardin.
abstract: Interferon regulatory factor 8 (IRF8), a member of the IRF transcription factor family, was recently implicated in vascular diseases. In the present study, using the mouse left carotid artery wire injury model, we unexpectedly observed that the expression of IRF8 was greatly enhanced in smooth muscle cells (SMCs) by injury. Compared with the wild-type controls, IRF8 global knockout mice exhibited reduced neointimal lesions and maintained SMC marker gene expression. We further generated SMC-specific IRF8 transgenic mice using an SM22α-driven IRF8 plasmid construct. In contrast to the knockout mice, mice with SMC-overexpressing IRF8 exhibited a synthetic phenotype and enhanced neointima formation. Mechanistically, IRF8 inhibited SMC marker gene expression through regulating serum response factor (SRF) transactivation in a myocardin-dependent manner. Furthermore, a coimmunoprecipitation assay indicated a direct interaction of IRF8 with myocardin, in which a specific region of myocardin was essential for recruiting acetyltransferase p300. Altogether, IRF8 is crucial in modulating SMC phenotype switching and neointima formation in response to vascular injury via direct interaction with the SRF/myocardin complex.
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
authors.forename: Shu-Min
authors.initials: SM
authors.lastname: Zhang
authors.forename: Lu
authors.initials: L
authors.lastname: Gao
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Zhang
authors.forename: Ran
authors.initials: R
authors.lastname: Zhang
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Zhu
authors.forename: Pi-Xiao
authors.initials: PX
authors.lastname: Wang
authors.forename: Song
authors.initials: S
authors.lastname: Tian
authors.forename: Da
authors.initials: D
authors.lastname: Yang
authors.forename: Ke
authors.initials: K
authors.lastname: Chen
authors.forename: Ling
authors.initials: L
authors.lastname: Huang
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Zhang
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D020212:Carotid Artery Injuries; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D015151:Immunoblotting; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D058426:Neointima / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011485:Protein Binding; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D000099185:Interferon Regulatory Factor-8; D000099251:Myocardin
chemical_list: D050835:Interferon Regulatory Factors; D009687:Nuclear Proteins; D026362:Serum Response Factor; D015534:Trans-Activators; D000099185:Interferon Regulatory Factor-8; D000099251:Myocardin