Smooth Muscle-Selective Inhibition of Nuclear Factor-kB Attenuates Smooth Muscle Phenotypic Switching and Neointima Formation Following Vascular Injury

Tadashi Yoshida, Maho Yamashita, Chihiro Horimai, Matsuhiko Hayashi

研究成果: Article査読

53 被引用数 (Scopus)

抄録

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 factorjB (NF-jB) pathway in vessels has been shown to be critical for the progression of vascular diseases, the cell-autonomous role of NF-jB within SMCs has not been fully understood. Methods and Results--We generated SMC-selective truncated IjB expressing (SM22α-Cre/IjBδN) mice, in which NF-jB was inhibited selectively in SMCs, and analyzed their phenotype following carotid injury. Results showed that neointima formation was markedly reduced in SM22α-Cre/IjBδN 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/IjBδN mice. Consistent with these findings, NF-jB activation by interleukin-1β (IL-1β) decreased expression of SMC differentiation markers as well as myocardin in cultured SMCs. Inhibition of NF-jB signaling by BAY 11-7082 attenuated repressive effects of IL-1β. Of interest, Kr€uppel-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-jB repressed myocardin by binding to the myocardin promoter region in concert with Klf4. Conclusions--These results provide novel evidence that activation of the NF-jB pathway cell-autonomously mediates SMC phenotypic switching and contributes to neointima formation following vascular injury.

本文言語English
論文番号e000230
ジャーナルJournal of the American Heart Association
2
3
DOI
出版ステータスPublished - 2013

ASJC Scopus subject areas

  • 循環器および心血管医学

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