The epigenetic factor PCAF regulates vascular inflammation and is essential for accelerated atherosclerosis development

Objective Genetic P300/CBP-associated factor (PCAF) variation affects resteno -sis-risk in patients. PCAF has lysine acetylase activity and promotes inflammation, which drives post-interventional vascular remodeling and accelerated atheroscle rosis development. We studied the contributing role of PCAF in post-interventional vascular remodeling. Methods and Results PCAF contribution to inflammation and vascular remodeling was assessed in macrophages in vitro and in a mouse model for vascular remode ling and accelerated atherosclerosis. PCAF regulates MHC class-II, but not MHC class-I expression in macrophages through CIITA, inducing a pro-inflammatory reac tion. PCAF -/- mice are used to show that PCAF deficiency is associated with 73.2% (p=0.001) reduction of intimal hyperplasia, intima/media ratio and luminal stenosis by preventing smooth muscle cell (SMC) accumulation. This was confirmed using the potent natural PCAF inhibitor garcinol in vivo which reduced arterial leukocyte and macrophage adherence and infiltration following injury and accelerated athe rosclerosis development by 71.9% (p=0.004) in operated hypercholesterolemic ApoE3*Leiden mice. This occurred due to downregulation of MCP-1 and TNFα ex pression by garcinol, similarly to PCAF siRNA, as demonstrated on cultured spleno cytes, SMCs and macrophages and in vivo. Conclusions These results identify a vital role for the epigenetic factor PCAF in the regulation of local inflammation after arterial injury, responsible for vascular remode ling and accelerated atherosclerosis development.

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