Abstract 14359: PCAF Plays an Important Role in Restenosis Development
Background Restenosis is the major drawback from percutaneous coronary interventions and inflammation plays an important role in this process. P300/CBP-associated factor (PCAF) has histone acetylating activity and stimulates inflammatory gene transcription. We have shown that genetic PCAF variation is associated with CHD mortality and restenosis. However, the role of PCAF in the development of restenosis remains unexplored.
Methods and Results To assess the role of PCAF in the development of restenosis, a femoral-arterial cuff mouse model is used in which intimal thicking develops after two weeks. The expression of the PCAF protein in the arterial wall was studied using immunohistochemistry and with quantitative mRNA analysis. PCAF was increasingly expressed in the lesions until 48 hours after surgery, after which expression was reduced. Using PCAF knockout mice, we show that PCAF deficiency is associated with 73.2% reduced neointima formation (PCAF+/+: 9.8±1.6 mm2, PCAF−/−: 2.6±0.4 mm2, p=0.001). Furthermore, when PCAF was therapeutically inhibited in hypercholesterolemic ApoE3*Leiden mice by local garcinol application in pluronic gel, a similar reduction of 71.9% in intimal thickening (control: 7.6±1.5 mm2, garcinol: 2.1±0.1 mm2, p=0.004) was observed.
Conclusion This is the first report showing that epigenetic control of inflammatory gene expression by modulation of histon aceteylation by regulation of PCAF can control restenosis development. Therefore PCAF could serve as therapeutic target against restenosis.
- © 2010 by American Heart Association, Inc.