Abstract 13061: Epigenetic Regulation By PCAF Moderates Arteriogenesis
Introduction: Collateral formation or arteriogenesis is a highly regulated process involving multiple factors and cell types, and the expression of various cytokines. Interventions using single factors have thus far not been as successful as we hoped for. In the current study we focus on the epigenetic regulation of a range of inflammatory factors involved in arteriogenesis, in particular on the role of the epigenetic factor PCAF. P300/CBP-associated factor (PCAF), also known as lysine acetyltransferase (KAT) 2B, has histone acetylating activity and promotes inflammatory gene transcription. We previously showed that genetic PCAF variation is associated with restenosis in patients and PCAF is causally involved in inflammatory vascular remodeling in a femoral-arterial cuff mouse model. However, the functional role of PCAF in the process of arteriogenesis is unknown.
Methods and Results: To assess the role of PCAF in arteriogenesis we use a murine hindlimb ischemia model. We demonstrate that PCAF mRNA expression after the surgical induction of hindlimb ischemia is reduced in both adductor and calf muscle of wildtype (WT) mice. PCAF deficient knock-out (PCAF−/−) mice show a hampered blood flow recovery measured by laser Doppler perfusion imaging. This is also observed by the increase in necrotic toes and reduced growth of α-smooth muscle actin positive vessels in the adductor muscle in PCAF−/− mice. The inflammatory TNFα response of circulating cells in PCAF−/− mice is strongly inhibited in an ex vivo whole blood LPS stimulation assay. Also pharmacological PCAF inhibition by garcinol results in lower TNFα levels. In vitro LPS stimulation of vascular smooth muscle cells (VSMCs) in both WT and PCAF−/− mice leads to less MCP-1 production in PCAF−/− mice. In addition results the administration of garcinol on WT VSMCs in a lower inflammatory response. PCAF inhibition or deficiency results in a hampered inflammatory reaction. The exact nature of the genes and cells that are regulated by PCAF in arteriogenesis is not yet known.
Conclusion: We conclude that there is a causal role for PCAF in inflammatory response and the lack of PCAF expression results in a hampered arteriogenesis.
- © 2011 by American Heart Association, Inc.