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.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01070-13.

ACKNOWLEDGMENTS

We greatly appreciate Xiang-jie Kong for his technical assistance with performing carotid arterial injuries.

This study was supported by the National Natural Science Foundation of China (grant numbers 81170086, 81100230, 81070089, and 81370365), the National Science and Technology Support Project (grant numbers 2011BAI15B02, 2012BAI39B05, and 2013YQ030923-05), the National Basic Research Program of China (grant number 2011CB503902), the Ministry of Education New Century Outstanding Talents Support Program (grant number NCET-10-0641), the Independent Scientific Research Project of Wuhan University (grant number 2012302020215), and the key project of the National Natural Science Foundation (grant number 81330005).