Inactivation of nuclear factor-Y inhibits vascular smooth muscle cell proliferation and neointima formation

Carlos Silvestre-Roig, Patricia Fernández, Vanesa Esteban, Óscar M. Pello, Ciro Indolfi, Cristina Rodríguez, Ricardo Rodríguez-Calvo, María Dolores López-Maderuelo, Gerhard Bauriedel, Randolph Hutter, Valentín Fuster, Borja Ibáñez, Juan M. Redondo, José Martínez-González, Vicente Andrés

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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. APPROACH AND 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.

Original languageEnglish
Pages (from-to)1036-1045
Number of pages10
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume33
Issue number5
DOIs
StatePublished - May 2013
Externally publishedYes

Keywords

  • atherosclerosis
  • cyclin B1
  • nuclear factor-Y
  • restenosis
  • vascular smooth muscle cell proliferation

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