Abstract 15515: Histone Deacetylase Inhibitors Attenuate Pulmonary Hypertension in Monocrotaline Rats
Background: Epigenetic programming, dynamically regulated by histone acetylation, has been implicated in vascular remodelling and may contribute to the pathogenesis of pulmonary arterial hypertension (PAH). Aberrant histone deacetylase (HDAC) activity has been shown in the lungs of PAH patients and pharmacological intervention with HDAC inhibitors can be beneficial in a chronic hypoxic rat model through mechanisms such as anti-proliferation and immune modulation. Herein we explored the pharmacologic effects of HDAC inhibitors in a more severe and irreversible experimental PH model, induced by monocrotaline (MCT), and aiming to define the underlying molecular mechanisms.
Methods: Two weeks after the MCT (60 mg/kg) injection, rats were treated with HDAC inhibitors, valproic acid (VPA), a class I HDAC inhibitor, or Vorinostat (SAHA), a broad-spectrum inhibitor of class I, II and IV HDACs, for two weeks. HDAC activity was examined by measuring levels of acetylated histone H3 and H4 and protein expression (P21, Bcl-2, survivin and TIMP-1) by Western blotting.
Results: In this study, treatment with VPA (300mg/kg/day) or SAHA (50mg/kg/day) significantly reduced MCT-induced pulmonary arterial pressure elevation (PAP, M4W: 40.4±3.4mmHg vs VPA: 27.6±2.4mmHg, SAHA: 21.7±1.4mmHg, p<0.001), right ventricular hypertrophy (RVH, M4W: 0.57±0.05 vs VPA: 0.41±0.03, SAHA: 0.32±0.00, p<0.01) and peripheral pulmonary vessel muscularization (M4W: 79.8±1.0% vs VPA: 72.0±1.1%, SAHA: 69.2±2.1%, p<0.01), but had no significant effects on systemic pressure. Treatment with VPA and SAHA led to increased p21 expression, reduced Bcl-2 and survivin expression (p<0.05) in lung homogenates and also elevated acetylation of histone H3 and H4, reflecting decreased activities of HDAC. Furthermore, these two inhibitors effectively reduced the abnormal overexpression of tissue inhibitor metalloproteinase-1 (TIMP-1, p<0.001), which has been implicated in excess extracellular matrix deposition and vascular remodelling in PAH.
Conclusions: HDAC inhibitors, VPA and SAHA, achieved anti-remodelling effects, leading to partial reversal of MCT-induced PH. The data add to the body of evidence suggesting HDACs are a promising therapeutic option for PAH.
- © 2012 by American Heart Association, Inc.