Activation of histone deacetylase 2: a novel strategy for reversing vascular dysfunction in atherogenesis (671.9)

Abstract

Although they are targeted by therapies for cancer, the implications of epigenetic modifications of histone tails by Histone Deacetylases (HDACs) for vascular homeostasis and cardiovascular diseases including atherosclerosis, diabetes and hypertension are unclear. The use of HDAC inhibitors in the treatment of cardiovascular disease is controversial, since the global HDAC inhibitor Trichostatin (TSA) was shown to accelerate atheroma formation in LDL‐receptor knockout mice.We have demonstrated that TSA causes impairment (~40%) of endothelium‐dependent vascular relaxation in isolated vascular rings. Using class‐specific biochemical HDAC inhibitors and siRNA‐mediated gene knockdown, we have identified HDAC2 as a specific, critical regulator of homeostasis in the vascular endothelium. We have also identified Arginase 2 (Arg2) as a major transcriptional target for HDAC2 that contributes to intimal dysfunction, by showing that vascular dysfunction mediated by HDAC inhibition was abolished by either pharmacologic inhibiton or genetic knockout of Arg2. Finally, inhibition of neddylation, a post‐translational modification that enhances ubiquitin‐mediated proteosomal degradation, increased the abundance of HDAC2 and caused decreased Arg2 activity. Hence, we hypothesize that atherogenic stimuli such as OxLDL and inflammation downregulate HDAC2 expression in vascular EC through NEDD8‐mediated enhancement of the proteosomal degradation of HDAC2. This reduction in HDAC2 results in the following cascade: increased Arg2 expression in EC, decreased L‐arginine concentration, impaired NO bioavailability via eNOS substrate depletion, and increased ROS. These events culminate in EC dysfunction and atherogenesis. In conclusion, activation of HDAC2 by pharmacologic agents or small molecule activators could serve as a potent strategy in an atheroprotective therapeutic regimen.Grant Funding Source: NIH