title: Inactivation of nuclear factor-Y inhibits vascular smooth muscle cell proliferation and neointima formation.
abstract: OBJECTIVE
  Atherosclerosis and restenosis are multifactorial diseases associated with abnormal vascular smooth muscle cell (VSMC) proliferation. Nuclear factor-Y (NF-Y) plays a major role in transcriptional activation of the CYCLIN B1 gene (CCNB1), a key positive regulator of cell proliferation and neointimal thickening. Here, we investigated the role of NF-Y in occlusive vascular disease.
  
  
  RESULTS
  We performed molecular and expression studies in cultured cells, animal models, and human tissues. We find upregulation of NF-Y and cyclin B1 expression in proliferative regions of murine atherosclerotic plaques and mechanically induced lesions, which correlates with higher binding of NF-Y to target sequences in the CCNB1 promoter. NF-YA expression in neointimal lesions is detected in VSMCs, macrophages, and endothelial cells. Platelet-derived growth factor-BB, a main inductor of VSMC growth and neointima development, induces the recruitment of NF-Y to the CCNB1 promoter and augments both CCNB1 mRNA expression and cell proliferation through extracellular signal-regulated kinase 1/2 and Akt activation in rat and human VSMCs. Moreover, adenovirus-mediated overexpression of a NF-YA-dominant negative mutant inhibits platelet-derived growth factor-BB-induced CCNB1 expression and VSMC proliferation in vitro and neointimal lesion formation in a mouse model of femoral artery injury. We also detect NF-Y expression and DNA-binding activity in human neointimal lesions.
  
  
  CONCLUSIONS
  Our results identify NF-Y as a key downstream effector of the platelet-derived growth factor-BB-dependent mitogenic pathway that is activated in experimental and human vasculoproliferative diseases. They also identify NF-Y inhibition as a novel and attractive strategy for the local treatment of neointimal formation induced by vessel denudation.
authors: Department of Epidemiology, Atherothrombosis and Imaging, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors: Carlos
authors: C
authors: Silvestre-Roig
authors: Patricia
authors: P
authors: Fernández
authors: Vanesa
authors: V
authors: Esteban
authors: Óscar M
authors: ÓM
authors: Pello
authors: Ciro
authors: C
authors: Indolfi
authors: Cristina
authors: C
authors: Rodríguez
authors: Ricardo
authors: R
authors: Rodríguez-Calvo
authors: María Dolores
authors: MD
authors: López-Maderuelo
authors: Gerhard
authors: G
authors: Bauriedel
authors: Randolph
authors: R
authors: Hutter
authors: Valentín
authors: V
authors: Fuster
authors: Borja
authors: B
authors: Ibáñez
authors: Juan M
authors: JM
authors: Redondo
authors: José
authors: J
authors: Martínez-González
authors: Vicente
authors: V
authors: Andrés
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology; D050197:Atherosclerosis / Q000209:etiology; D000077214:Becaplermin; D023081:CCAAT-Binding Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D056744:Cyclin B1 / Q000235:genetics; D042783:Endothelial Cells / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D058426:Neointima / Q000209:etiology* / Q000628:therapy; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D001057:Apolipoproteins E; D023081:CCAAT-Binding Factor; C534699:CCNB1 protein, human; D056744:Cyclin B1; D020574:Proto-Oncogene Proteins c-sis; C402244:nuclear factor Y; D000077214:Becaplermin