TRAIL promotes VSMC proliferation and neointima formation in a FGF-2-, Sp1 phosphorylation-, and NFkappaB-dependent manner.
BACKGROUND
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.


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)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.
Centre for Vascular Research, The University of New South Wales, Sydney NSW 2052, Australia.
Jeffrey
J
Chan
Leonel
L
Prado-Lourenco
Levon M
LM
Khachigian
Martin R
MR
Bennett
Belinda A
BA
Di Bartolo
Mary M
MM
Kavurma
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D049109:Cell Proliferation; D002478:Cells, Cultured; D005263:Femoral Artery / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D017539:Tunica Intima / Q000378:metabolism* / Q000473:pathology
D016328:NF-kappa B; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016329:Sp1 Transcription Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D016222:Fibroblast Growth Factor 2