Inactivation of Nuclear Factor-Y Inhibits Vascular Smooth Muscle Cell Proliferation and Neointima Formation
Por:
Silvestre-Roig, C, Fernandez, P, Esteban, V, Pello, OM, Indolfi, C, Rodriguez, C, Rodriguez-Calvo, R, Lopez-Maderuelo, MD, Bauriedel, G, Hutter, R, Fuster, V, Ibanez, B, Redondo, JM, Martinez-Gonzalez, J, Andres, V
Publicada:
1 may 2013
Resumen:
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. (Arterioscler Thromb Vasc Biol. 2013; 33:1036-1045.)
Filiaciones:
Silvestre-Roig, C:
CNIC, Dept Epidemiol Atherothrombosis & Imaging, Madrid 28029, Spain
Fernandez, P:
CNIC, Dept Epidemiol Atherothrombosis & Imaging, Madrid 28029, Spain
Esteban, V:
CNIC, Dept Epidemiol Atherothrombosis & Imaging, Madrid 28029, Spain
Pello, OM:
CNIC, Dept Epidemiol Atherothrombosis & Imaging, Madrid 28029, Spain
Indolfi, C:
Magna Graecia Univ Catanzaro, Dept Med & Surg Sci, Div Cardiol, URT CNR, Catanzaro, Italy
Rodriguez, C:
CSIC, Ctr Invest Cardiovasc, Inst Catala Ciencies Cardiovasc, Inst Invest Biomed St Pau, Barcelona, Spain
Rodriguez-Calvo, R:
CSIC, Ctr Invest Cardiovasc, Inst Catala Ciencies Cardiovasc, Inst Invest Biomed St Pau, Barcelona, Spain
Lopez-Maderuelo, MD:
CNIC, Dept Vasc Biol & Inflammat, Madrid 28029, Spain
Bauriedel, G:
Univ Bonn, Ctr Heart, Dept Cardiol, Bonn, Germany
Hutter, R:
Mt Sinai Sch Med, Zena & Michael A Wiener Cardiovasc Inst, New York, NY USA
Fuster, V:
CNIC, Dept Epidemiol Atherothrombosis & Imaging, Madrid 28029, Spain
Mt Sinai Sch Med, Zena & Michael A Wiener Cardiovasc Inst, New York, NY USA
Ibanez, B:
CNIC, Dept Epidemiol Atherothrombosis & Imaging, Madrid 28029, Spain
Univ Complutense Madrid, Cardiovasc Inst, Hosp Clin San Carlos, Madrid, Spain
Redondo, JM:
CNIC, Dept Vasc Biol & Inflammat, Madrid 28029, Spain
Martinez-Gonzalez, J:
CSIC, Ctr Invest Cardiovasc, Inst Catala Ciencies Cardiovasc, Inst Invest Biomed St Pau, Barcelona, Spain
Andres, V:
CNIC, Dept Epidemiol Atherothrombosis & Imaging, Madrid 28029, Spain
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