Abstract 19388: HDAC6 Inhibition Potential in Pulmonary Arterial Hypertension
Introduction: Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by the elevation of mean pulmonary arterial pressure. Pulmonary arterial smooth muscle cells (PASMCs) from PAH patients exhibit a cancer-like pro-proliferative and anti-apoptotic phenotype leading to development of progressive pulmonary artery remodeling. The histone deacetylase 6 (HDAC6) is mainly cytoplasmic and involved primarily in “non-histone” functions. Previous studies have shown that HDAC6 plays critical roles on many cellular processes related to cancer.
Hypothesis: HDAC6 inhibition corrects the abnormal phenotype of PAH-PASMCs and improves PAH.
Methods and Results: Using a multidisciplinary and translational approach, we demonstrated that HDAC6 is 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, ACY-775 or siHDAC6 dose-dependently increased α-tubulin acetylation and decreased apoptosis resistance (Annexin-V; p<0.05) and proliferation (Ki67; p<0.01) of PAH-PASMCs, without affecting control PASMCs. In vitro, inhibition of HDAC6 increases DNA damage (γH2AX, WB) and promotes the accumulation of ubiquitinated protein aggregates potentially toxic for the cell (ubiquitin, WB and IF). Finally, in both monocrotaline and sugen/hypoxia rat models of PAH, we demonstrated that HDAC6 inhibition using Tubastatin A (25mg/kg/day, 14 days, i.p.) improves pulmonary hemodynamic (p<0.01) and reduced PA remodeling (p<0.05).
Conclusions: We provide evidence that HDAC6 is upregulated in human PAH and contribute to the proliferative and anti-apoptotic phenotype of PAH-PASMCs. HDAC6 inhibition may represent a novel and attractive avenue for reversing PAH avoiding the adverse off-target effects of pan-HDAC inhibitors. The susceptibility of HDAC6 KO mice to develop PAH following hypoxia exposure is currently under investigation.
Author Disclosures: F. Potus: None. O. Boucherat: None. S. Chabot: None. A. Bourgeois: None. C. Lambert: None. S. Breuils-Bonnet: None. R. Paradis: None. S. Provencher: None. S. Bonnet: None.
- © 2016 by American Heart Association, Inc.