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

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere000230
JournalJournal of the American Heart Association
Volume2
Issue number3
DOIs
Publication statusPublished - 2013

Fingerprint

Neointima
Vascular System Injuries
Smooth Muscle Myocytes
Smooth Muscle
Cell Differentiation
Differentiation Antigens
Interleukin-1
Vascular Diseases
Chromatin Immunoprecipitation
Wounds and Injuries
Genetic Promoter Regions
myocardin
Atherosclerosis
Transcription Factors
Down-Regulation
Endothelial Cells
Macrophages
Cell Proliferation
Lymphocytes
Phenotype

Keywords

  • Klf4
  • Myocardin
  • Nuclear factor-kB
  • Smooth muscle cells

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

Cite this

Smooth Muscle-Selective Inhibition of Nuclear Factor-kB Attenuates Smooth Muscle Phenotypic Switching and Neointima Formation Following Vascular Injury. / Yoshida, Tadashi; Yamashita, Maho; Horimai, Chihiro; Hayashi, Matsuhiko.

In: Journal of the American Heart Association, Vol. 2, No. 3, e000230, 2013.

Research output: Contribution to journalArticle

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AB - 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.

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