Abstract 665: Activation of Histone Deacetylase 2: A Novel Strategy for Reversing Vascular Dysfunction in Atherogenesis

Abstract

Arginase 2 is a critical target in atherosclerosis as it regulates both endothelial NO, fibrosis and inflammation. The increase in Arg2 activity with endothelial cell activation is dependent on both early post-translational dependent mechanisms as well as a later increase in Arg 2 expression. The regulators of Arg2 transcription in the endothelium have not been characterized. The goal of current study is to determine the role of specific HDACs in the regulation of endothelial Arg2 transcription and thereby endothelial function. The global HDAC inhibitor, trichostatin (TSA) both time and concentration-dependently increased Arg2 mRNA, protein levels and activity in both HAECs and mouse aortic rings, a process that leads to Arg2-dependent endothelial dysfunction. TSA and atherogenic stimulus enhances activity of common promoter regions of Arg 2. All non-selective Class I HDAC inhibitors (TSA, Scriptaid, varinostat) enhanced Arg2 expression, while only the, the HDCA 1 and 2 selective inhibitor, mocetinostat (MGCD) enhances Arg2 expression. Overexpression of HDAC 2, 3 or 8 in HAECs have no effect on Arg 2 expression while HDAC2 cDNA overexpression concentration-dependently suppresses Arg2 expression. Conversely, siRNA knockdown of HDAC2 enhances Arg2 expression. Additionally like TSA, mouse aortic rings pre-incubated with MGCD resulted in endothelial dysfunction. Finally HDAC inhibition with TSA decreased endothelial NO and increased ROS production in an arginase-inhibitable manner. In conclusion, HDAC2 is critical regulator of Arg2 expression thereby regulating endothelial NO and ROS production, and consequently endothelial function. Overexpression or activation of HDAC2 thus represents a novel therapy for the prevention and treatment of endothelial dysfunction and atherosclerosis.