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.