Abstract 216: Hdac2 Modulates Atherosclerosis

Abstract

Objective: We recently described a novel regulatory role for histone deacetylase 2 (HDAC2) in vascular endothelial cell protection against the known endothelial injury stimulus Oxidize Low Density Lipoprotein (OxLDL). The goal of current study is to determine the effects of endothelial-specific HDAC2 overexpression on endothelial dysfunction and atherogenesis in vivo . Approach and Results: To study the effect of endothelial HDAC2 overexpression on vascular function and atherogenesis, we generated and characterized an endothelial specific human HDAC2 overexpressing transgenic mouse (HDAC2-Tg) under the control of the tie2 promoter. The founder HDAC2-overexpressing mice appear to have a normal phenotype- normal weight, mean arterial blood pressure (MAP) and pulse wave velocity (PWV). Isolated intact aortas from endothelial-specific overexpressing HDAC2 transgenic mice (HDAC2-Tg) exhibited a healthier vascular function profile with higher nitric oxide levels and less OxLDL-mediated vascular dysfunction. Further, we induced atherogenesis in C57BL6 and HDAC2-Tg mice by injecting adeno-associated viruses (AAV) encoding PCSK9 (D377Y) under the control of a liver-specific promoter by tail vein injection followed by high fat diet regimen for 12 weeks and measured endothelium-dependent vasorelaxation in isolated blood vessels, pulse wave velocity, an index of vascular stiffness and mean arterial blood pressure. HDAC2-Tg exhibited protected endothelial dependent vascular relaxation and no significant changes in MAP and PWV as compared to control mice. Conclusion: HDAC2 is a critical regulator of endothelial function. Overexpression or activation of HDAC2 represents a novel therapy for endothelial dysfunction and atherosclerosis.