Smooth muscle-selective inhibition of nuclear factor-κB attenuates smooth muscle phenotypic switching and neointima formation following vascular injury

Tadashi Yoshida, Maho Yamashita, Chihiro Horimai, Matsuhiko Hayashi
Journal of the American Heart Association 2013, 2 (3): e000230

BACKGROUND: Vascular proliferative diseases such as atherosclerosis are inflammatory disorders involving multiple cell types including macrophages, lymphocytes, endothelial cells, and smooth muscle cells (SMCs). 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 SMCs has not been fully understood.

METHODS AND RESULTS: We generated SMC-selective truncated IκB expressing (SM22α-Cre/IκBΔN) mice, in which NF-κB was inhibited selectively in SMCs, and analyzed their phenotype following carotid injury. Results showed that neointima formation was markedly reduced in SM22α-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 SM22α-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 SMCs. 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.

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