Histone deacetylase 6 (HDAC6) has pleiotropic influence on cytoplasmic proteins involved in oncogenesis, immunity and degeneration. Abrrant expression of HDAC6 was demonstrated in lungs and right ventricle in human and rodent models of pulmonary arterial hypertension (PAH) and inhibition of HDAC6 has emerged as a potential treatment. We introduced a novel HDAC6 inhibitor, C1A, in PAH models and explored its role in immune modulation and autophagy pathway. Superior to other available selective HDAC inhibitors, C1A demonstrates activities on a restricted number of genes in vivo (<0.065%) and a favourable pharmacokinetic profile, granting minimal side effects and clinical potentials.
Methods and Results:
PAH model was established by injecting monocrotaline (MCT, 60 mg/kg) to male rats for two weeks, followed by treatment with C1A (5mg /kg/day or 10 mg/kg/day) or vehicle for continuous two weeks. PBMCs were isolated from whole blood taken from humans and rats using Ficoll-Paque gradient centrifugation. HDAC6 expression, but not HDAC1, was significantly increased in PBMCs from idiopathic PAH patients as well as from MCT rats, along with decreased acetylation level of α-tubulin, which is a specific indicator of HDAC6 activity. Treatment with C1A reduced the MCT-induced elevated pulmonary arterial pressure (MCT: 38.4±1.9mmHg vs Low C1A: 34.0±2.6mmHg, High C1A: 17.9±1.3mmHg, p<0.0001), right ventricular hypertrophy (MCT: 0.50±0.02 vs Low C1A: 0.40±0.02, High C1A: 0.30±0.01, p<0.0001) and pulmonary vascular remodelling (MCT: 78.7±0.6% vs Low C1A: 69.4±2.0%, High C1A: 65.8±3.3%, p<0.0001). In MCT rat lungs, C1A resolved the autophagy-related protein expression such as light chain-3 (LC3), p62 and ATG5/12. Furthermore, C1A inhibited PDGF-stimulated proliferation of pulmonary artery smooth muscle cells in vitro, associated with increased acetylation of α-tubulin and alternations of autophagy substrates.
HDAC6 is implicated in PAH pathogenesis. Selective inhibitor C1A modulates autophagy and could be a promising therapeutic option for PAH patients