Abstract 235: Epigenetic Mediator PCAF Moderates Arteriogenesis

Introduction: Collateral artery formation or arteriogenesis is a highly regulated process involving multiple factors and cell types, with a pronounced role for the inflammatory system. In the current study we focus on a transcriptional co-activator P300/CBP-associated factor (PCAF). PCAF, also known as lysine acetyltransferase (KAT)2B, has histone acetylating activity and promotes inflammatory gene transcription. The functional role of PCAF in the process of arteriogenesis is unknown. Methods and results: To assess the role of PCAF in arteriogenesis we used a murine hindlimb ischemia model. We demonstrated that PCAF mRNA expression after the surgical induction of hindlimb ischemia is reduced in both adductor and calf muscle of wildtype (WT) mice. In vitro, the lack of PCAF resulted in a reduced inflammatory response in whole blood, vascular smooth muscle cell and splenocyte stimulation assays. In vivo, the PCAF -/- phenotype showed a hampered blood flow recovery after double ligation of the femoral artery, measured by laser Doppler perfusion imaging (ratio 0.42±0.08 in PCAF -/- vs 0.71±0.08 in WT at day 7) and by immunohistological analysis of collateral arteries. Also pharmacological inhibition of PCAF by local administration of garcinol reduced blood flow recovery after single femoral artery ligation (ratio 0.76±0.07 with garcinol vs 1.07±0.06 in control at day 7). PCAF deficiency influences arteriogenesis locally by disturbing the regulation of pro-arteriogenic genes in the ischemic adductor muscle. Moreover PCAF -/- mice showed a different post-ischemic regulation of circulating inflammatory cells. In particular, PCAF -/- mice showed reduced numbers of circulating monocytes (0.12*10E6/mL in PCAF -/- vs 0.37*10E6/mL in WT) and fewer monocytes were detected around the collateral arteries already one day after surgery. Conclusions: We conclude that PCAF regulates arteriogenesis by modulating the post-ischemic inflammatory response.