TRAIL promotes VSMC proliferation and neointima formation in a FGF-2-, Sp1 Phosphorylation-, and NFκB-Dependent Manner

Jeffrey Chan, Leonel Prado-Lourenco, Levon M. Khachigian, Martin R. Bennett, Belinda A. Di Bartolo, Mary M. Kavurma

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60 Citations (Scopus)

Abstract

RATIONALE: TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is well reported as an inducer of apoptosis in tumor models; however, its role and function in vivo in atherosclerosis and vascular injury has not been established. OBJECTIVE: We sought to study the function of TRAIL in cardiovascular pathology and its regulation in vivo. METHODS AND RESULTS: Here, we show that TRAIL was upregulated in medial vascular smooth muscle cells (VSMCs) 24 hours following perivascular cuff placement around femoral arteries of mice. We also show that TRAIL mRNA and promoter activity was induced in VSMCs following in vitro mechanical injury. Intimal thickening 15 days after cuff placement was reduced 2-to 3-fold in TRAIL compared to wild-type mice and was reversible by administration of recombinant TRAIL. Additionally, reduced VSMC proliferation was observed in injured arteries of TRAIL mice. Fibroblast growth factor (FGF)-2, a potent growth factor released following vascular injury, was also reduced in arteries of TRAIL mice, and VSMCs isolated from these animals did not respond to FGF-2 in vitro. Injury and FGF-2 regulated TRAIL transcriptional activity via 2 specificity protein (Sp)1 elements in the proximal TRAIL promoter, a binding site also shared by nuclear factor (NF)κB. Mutational studies confirmed a role for Sp1 in injury-and FGF-2-inducible TRAIL transcription. Furthermore, increased NFκB expression after injury transactivated the TRAIL promoter. Interestingly, following mechanical injury, Sp1 phosphorylation (Thr453) and an increase in the physical interaction of p-Sp1(Thr453) with NFκB was observed. CONCLUSIONS: We conclude that TRAIL induction involves FGF-2, Sp1-phosphorylation and NFκB and that TRAIL promotes VSMC proliferation and neointima formation after arterial injury.

Original languageEnglish
Pages (from-to)1061-1071
Number of pages11
JournalCirculation Research
Volume106
Issue number6
DOIs
Publication statusPublished - 1 Apr 2010

Keywords

  • Injury
  • TRAIL
  • Transcriptional regulation
  • VSMC proliferation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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