Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/7748
Inactivation of nuclear factor-Y inhibits vascular smooth muscle cell proliferation and neointima formation
Silvestre-Roig, Carlos CNIC | Fernandez, Patricia CNIC | Esteban, Vanesa CNIC | Pello, Oscar M CNIC | Indolfi, Ciro | Rodríguez, Cristina | Rodríguez-Calvo, Ricardo | Lopez-Maderuelo, Dolores CNIC | Bauriedel, Gerhard | Hutter, Randolph | Fuster, Valentin CNIC | Ibanez, Borja CNIC | Redondo, Juan Miguel CNIC | Martínez-González, José | Andres, Vicente CNIC
Arterioscler Thromb Vasc Biol. 2013; 33(5):1036-45
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.
Animals | Apolipoproteins E | Atherosclerosis | Becaplermin | CCAAT-Binding Factor | Cell Proliferation | Cells, Cultured | Cyclin B1 | Endothelial Cells | Humans | Male | Mice | Mice, Inbred C57BL | Muscle, Smooth, Vascular | Neointima | Proto-Oncogene Proteins c-sis | Rats | Rats, Wistar