Pharmacological Effect of Histone Deacetylase Inhibitors on Pulmonary Arterial Hypertension

Abstract

Pulmonary hypertension (PH) is characterized by structural remodelling of pulmonary arteries and arterioles, the result, at least in part, of excessive cell proliferation, resistance to cell death and hyperactive inflammatory reactions. Currently available treatments targeting the hyper-proliferative and pro-inflammatory pathology are limited. Epigenetic programming, dynamically regulated by histone acetylation, is an important mechanism for cell proliferation and survival. Aberrant changes of histone acetylation, modulated by histone deacetylase (HDAC), are shown in many proliferative and inflammatory disorders, especially cancer, and may contribute to the phenotypical changes in remodelling and overall to the development of PH. Hypothetically, HDAC inhibitors have therapeutic potential by reversing the imbalance of acetylation. I examined the correlations between HDAC expression and PH development, followed by evaluation of the pharmacological effects and possible mechanisms of two HDAC inhibitors, class I inhibitor valproic acid (VPA) and pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA), on animal models and cellular systems. Altered HDAC expression, specifically increased HDAC1 and HDAC5 along with elevation of anti-apoptotic marker Bcl-2, were found in lungs from patients with idiopathic pulmonary arterial hypertension and chronically hypoxic rats. In in vivo studies, VPA and SAHA ameliorated the established PH in both hypoxia- and monocrotalineinduced PH rat models, by reducing pulmonary arterial pressure, right ventricular hypertrophy and pulmonary vascular muscularization, in parallel with increasing histone acetylation. In in vitro studies, VPA and SAHA inhibited stimulated cell growth of pulmonary artery smooth muscle cells and cytokine release from endothelial cells. Biochemical analysis indicated these two inhibitors exert anti-proliferative effects comprising cell cycle arrest by upregulation of p21 and apoptotic induction by downregulation of Bcl-2. Collectively, this study shows the contribution of abnormal HDAC activity to vascular pathology of PH and provides a preclinical basis to further explore the therapeutic potential of HDAC inhibitors in human PH.