| First Author | Yoshida T | Year | 2013 |
| Journal | J Am Heart Assoc | Volume | 2 |
| Issue | 3 | Pages | e000230 |
| PubMed ID | 23702880 | Mgi Jnum | J:273494 |
| Mgi Id | MGI:6287999 | Doi | 10.1161/JAHA.113.000230 |
| Citation | Yoshida T, et al. (2013) Smooth muscle-selective inhibition of nuclear factor-kappaB attenuates smooth muscle phenotypic switching and neointima formation following vascular injury. J Am Heart Assoc 2(3):e000230 |
| abstractText | 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-kappaB (NF-kappaB) pathway in vessels has been shown to be critical for the progression of vascular diseases, the cell-autonomous role of NF-kappaB within SMCs has not been fully understood. METHODS AND RESULTS: We generated SMC-selective truncated IkappaB expressing (SM22alpha-Cre/IkappaBDeltaN) mice, in which NF-kappaB was inhibited selectively in SMCs, and analyzed their phenotype following carotid injury. Results showed that neointima formation was markedly reduced in SM22alpha-Cre/IkappaBDeltaN 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 SM22alpha-Cre/IkappaBDeltaN mice. Consistent with these findings, NF-kappaB activation by interleukin-1beta (IL-1beta) decreased expression of SMC differentiation markers as well as myocardin in cultured SMCs. Inhibition of NF-kappaB signaling by BAY 11-7082 attenuated repressive effects of IL-1beta. Of interest, Kruppel-like factor 4 (Klf4), a transcription factor critical for regulating SMC differentiation and proliferation, was also involved in IL-1beta-mediated myocardin repression. Promoter analyses and chromatin immunoprecipitation assays revealed that NF-kappaB repressed myocardin by binding to the myocardin promoter region in concert with Klf4. CONCLUSIONS: These results provide novel evidence that activation of the NF-kappaB pathway cell-autonomously mediates SMC phenotypic switching and contributes to neointima formation following vascular injury. |
