Interferon Regulatory Factor 8 Modulates Phenotypic Switching of Smooth Muscle Cells by Regulating the Activity of Myocardin

Abstract

e 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 SMCspecific IRF8 transgenic mice using an SM22␣-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.

The interferon regulatory factors as novel potential targets in the treatment of cardiovascular diseases

“…In addition to participating in cardiac hypertrophy and neuron survival, SRF and its co-activator, myocardin, play essential roles in SMC differentiation and phenotypic switching (Camoretti-Mercado et al, 2003;Miano, 2003;Yoshida et al, 2003). Recent studies from our group have demonstrated that IRF8 can act as an accelerated regulator of neointimal formation through a direct interaction with the SRF/myocardin complex, thereby regulating SRF transactivation to inhibit the expression of SMC-marker genes (Zhang et al, 2014a).…”

“…In addition to participating in cardiac hypertrophy and neuron survival, SRF and its co-activator, myocardin, play essential roles in SMC differentiation and phenotypic switching (Camoretti-Mercado et al, 2003;Miano, 2003;Yoshida et al, 2003). Recent studies from our group have demonstrated that IRF8 can act as an accelerated regulator of neointimal formation through a direct interaction with the SRF/myocardin complex, thereby regulating SRF transactivation to inhibit the expression of SMC-marker genes (Zhang et al, 2014a).Most recently, IRF9 was investigated in our research laboratory because of its regulatory effects on vascular remodelling in response to both in vivo and in vitro stimuli. Compared with controls, IRF9 protein expression is significantly higher in human femoral artery specimens with in-stent restenosis, a wire injury-induced neointimal formation mouse model, and PDGF-BB-stimulated VSMC.…”

Interferon Regulatory Factor Signalings in Cardiometabolic Diseases

“…145 However, in recent years, IRF8 expression was observed in VSMCs and was greatly increased after PDGF-BB administration in vitro or after wire injury in vivo. 100 On the basis of gain-and loss-of-function approaches, suppressed phenotypic switching of VSMCs was found in IRF8-deficient mice after vascular injury, whereas IRF8 overexpression promoted the transformation of VSMCs from a contractile phenotype to a synthetic phenotype compared with WT controls. 100 Further molecular biological studies elucidated the potential mechanism underlying the IRF8-mediated exacerbation of mechanical stress-induced vascular lesions.…”

“…100 On the basis of gain-and loss-of-function approaches, suppressed phenotypic switching of VSMCs was found in IRF8-deficient mice after vascular injury, whereas IRF8 overexpression promoted the transformation of VSMCs from a contractile phenotype to a synthetic phenotype compared with WT controls. 100 Further molecular biological studies elucidated the potential mechanism underlying the IRF8-mediated exacerbation of mechanical stress-induced vascular lesions. During the development and maintenance of VSMCs, myocardin acts as a prominent regulator by interacting with its coactivator serum response factor (SRF) and by modulating the activation of the SRF/CArG axis.…”

Interferon Regulatory Factor 1 Is Required for Cardiac Remodeling in Response to Pressure Overload

“…11,27,[43][44][45] Importantly, our recent findings demonstrated that IRF3, IRF7, IRF8, and IRF9 function as protective factors by inactivating extracellular signalregulated kinases 1 and 2, inhibitor of κB kinase-β, nuclear factor of activated T cell c1, or myocardin in the process of pressure overload-induced cardiac hypertrophy, respectively, 3,[12][13][14] whereas IRF4 plays an opposite role by activating the transcription of cAMP response element-binding protein in the heart. 5 In present study, we demonstrated that IRF1 accelerated pressure overload-induced cardiac hypertrophy by the direct activation of iNOS.…”