TRAIL promotes VSMC proliferation and neointima formation in a FGF-2-, Sp1 phosphorylation-, and NFkappaB-dependent manner.
Circ Res
; 106(6): 1061-71, 2010 Apr 02.
Article
em En
| MEDLINE
| ID: mdl-20150555
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 ANDRESULTS:
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)kappaB. Mutational studies confirmed a role for Sp1 in injury- and FGF-2-inducible TRAIL transcription. Furthermore, increased NFkappaB 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 NFkappaB was observed.CONCLUSIONS:
We conclude that TRAIL induction involves FGF-2, Sp1-phosphorylation and NFkappaB and that TRAIL promotes VSMC proliferation and neointima formation after arterial injury.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fator 2 de Crescimento de Fibroblastos
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NF-kappa B
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Fator de Transcrição Sp1
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Túnica Íntima
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Miócitos de Músculo Liso
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Proliferação de Células
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Ligante Indutor de Apoptose Relacionado a TNF
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Músculo Liso Vascular
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Circ Res
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Austrália