Abstract 14331: Role for HDAC6 in Pulmonary Arterial Hypertension

Abstract

Background: Pulmonary arterial smooth muscle cells (PASMCs) from pulmonary arterial hypertension (PAH) patients exhibit a pro-proliferative, pro-migratory and anti-apoptotic phenotype mediated, at least in part, by survivin overexpression, leading to the development of progressive pulmonary artery (PA) remodeling. This results in right ventricle (RV) hypertrophy and failure. For many years, the cytoplasmic class IIb histone deacetylase 6 (HDAC6), which mainly functions as a α-tubulin deacetylase has been understudied. Several cancer studies have demonstrated that HDAC6 cooperates with the Heat Shock Protein 90 (HSP90) and regulates many signaling pathways involved in cancer and PAH development. In the cardiovascular field, HDAC6 upregulation has been associated with heart failure. We hypothesized that specific HDAC6 inhibition corrects the abnormal phenotype of PAH-PASMCs and improves RV function. Method/Results: Using a multidisciplinary and translational approach, we demonstrated that both HDAC6 and HSP90 are upregulated (Wb; p<0.01) in the lungs, distal PAs, and PASMCs from PAH patients (n=5) compared to controls (n=5). HDAC6 inhibition using Tubastatin A dose-dependently increased α-tubulin acetylation and decreased PAH-PASMC migration (scratch test; p<0.05), apoptosis resistance (Annexin-V; p<0.05) and proliferation (Ki67; p<0.01). Tubastatin A also reduced the expression of survivin in PAH-PASMCs (Wb). Similar effects were observed after HSP90 inhibition with AT13387, which also reduced HDAC6 expression in PAH-PASMCs (Wb) suggesting that a HSP90-dependent mechanism may account for HDAC6 upregulation. Within the heart, HDAC6 was exclusively expressed in human decompensated RV from PAH patients (n=5) and not in control RV (Wb, p<0.01). Conclusion: We provide evidence that HSP90 and HDAC6 are upregulated in human PAH and contribute to the proliferative, migratory and anti-apoptotic phenotype of PAH-PASMCs. Moreover, HDAC6 is specifically increased in the RV of PAH patients, suggesting that specific HDAC6 inhibition may represent a novel and attractive target in PAH for the treatment of both PA remodeling and RV failure. The therapeutic potential of HDAC6 inhibition in a PAH rat model is currently under investigation.