Deficiency of transcription factor E4BP4 suppresses neointimal formation after vascular injury.

Abstract

BACKGROUND AND AIMS: Adventitial inflammation is involved in the onset of Takayasu arteritis (TAK) and the formation of pathological conditions. E4BP4 is a transcription factor involved in regulating circadian rhythms and cell viability, and it has been reported that E4BP4 regulates inflammation. Therefore, we decided to investigate the role of E4BP4 in neointimal formation after adventitial inflammation induced by cuff injury. METHODS: Using E4BP4-deficient (E4BP4-/-) and wild-type (WT) mice, we investigated neointimal formation 2 weeks after femoral artery injury induced by an external vascular cuff model. Intimal and medial area were measured, and the intima/media ratio was calculated. RESULTS: The mean intimal area and the intima/media ratio of E4BP4-/- mice decreased by 86 % and 97%, respectively, compared with WT mice. Immunohistochemistry for NK cell (NKp46) revealed the percentage of NKp46 positive area in the adventitia of E4BP4-/- mice was significantly lower compared with WT mice at 14 days post-injury. Furthermore, the positive area of CD8α (cytotoxic T lymphocyte (CTL)), IL-6, TNF-α and IFN-γ in the intima of E4BP4-/- mice was much smaller than those of WT mice. CONCLUSIONS: Deficiency of E4BP4 reduced the inflammatory cytokines and suppressed neointimal formation after adventitial inflammation. We also observed a decrease in both NKp46 and CD8α, suggesting that proliferation of NK cell and CTL is impaired by E4BP4 deficiency. The present study is the first to demonstrate that E4BP4 plays an important role in the increase of neointimal formation after inflammation in vivo, thus suggesting that E4BP4 inhibition may represent a useful strategy to inhibit vascular inflammation, such as TAK.