Abstract
Introduction: Pulmonary hypertension (PH) is a progressive disease resulting in right heart dysfunction and failure. It is characterized by pulmonary vascular remodeling, which is mediated by dysregulation of proliferation, migration and apoptosis of vascular cells. Epigenetic changes, such as histone acetylation, influence gene expression and play a role in several cellular processes. The balance between the acetylated/deacetylated states of histones is partly mediated by histone deacetylases (HDACs).
Aim: We intend to study the role of classIIa HDACs (HDAC4, HDAC5, HDAC7, HDAC9) in the pathogenesis of PH, focusing on pulmonary arterial smooth muscle cells (PASMCs).
Methods: Analysis of HDACs expression in human samples from donors and idiopathic PAH patients as well as in chronic hypoxia-induced PH murine model was carried out by RT-PCR, Western blotting and immunohistochemistry. The effects on proliferation and apoptosis of selective siRNA on cultured PASMCs were investigated.
Results: The expression levels of HDAC7 and HDAC9 are upregulated in human PH samples as well as in the murine model. Immunohistochemistry showed different localization pattern, with HDAC7 mostly expressed in PASMC and HDAC9 in PASMCs, adventitial fibroblasts and infiltrating cells. In vitro experiments suggest that the expression and cellular localization of these HDACs are regulated by hypoxia. Selective siRNAs are able to block cellular responses to hypoxia, interfering with HIF1α signaling pathway. In addition, they increase the apoptosis of PASMCs under hypoxia.
Conclusions: Our findings suggest that classIIa HDACs are involved in PH pathogenesis and their specific inhibition may represent a therapeutic target.
- © 2014 ERS