Smooth Muscle–Selective Inhibition of Nuclear Factor‐κB Attenuates Smooth Muscle Phenotypic Switching and Neointima Formation Following Vascular Injury

Abstract

Background Vascular proliferative diseases such as atherosclerosis are inflammatory disorders involving multiple cell types including macrophages, lymphocytes, endothelial cells, and smooth muscle cells ( SMC s). Although activation of the nuclear factor‐κB ( NF ‐κB) pathway in vessels has been shown to be critical for the progression of vascular diseases, the cell‐autonomous role of NF ‐κB within SMC s has not been fully understood. Methods and Results We generated SMC ‐selective truncated IκB expressing ( SM 22α‐Cre/IκBΔN) mice, in which NF ‐κB was inhibited selectively in SMC s, and analyzed their phenotype following carotid injury. Results showed that neointima formation was markedly reduced in SM 22α‐Cre/IκBΔN mice after injury. Although vascular injury induced downregulation of expression of SMC differentiation markers and myocardin , a potent activator of SMC differentiation markers, repression of these markers and myocardin was attenuated in SM 22α‐Cre/IκBΔN mice. Consistent with these findings, NF ‐κB activation by interleukin‐1β ( IL ‐1β) decreased expression of SMC differentiation markers as well as myocardin in cultured SMC s. Inhibition of NF ‐κB signaling by BAY 11‐7082 attenuated repressive effects of IL ‐1β. Of interest, Krüppel‐like factor 4 (Klf4), a transcription factor critical for regulating SMC differentiation and proliferation, was also involved in IL ‐1β‐mediated myocardin repression. Promoter analyses and chromatin immunoprecipitation assays revealed that NF ‐κB repressed myocardin by binding to the myocardin promoter region in concert with Klf4. Conclusions These results provide novel evidence that activation of the NF ‐κB pathway cell‐autonomously mediates SMC phenotypic switching and contributes to neointima formation following vascular injury.