Histone Deacetylation Inhibition in Pulmonary Hypertension

Abstract

Background Epigenetic programming, dynamically regulated by histone acetylation, is a key mechanism regulating cell proliferation and survival. Little is known about the contribution of histone deacetylase (HDAC) activity to the development of pulmonary arterial hypertension (PAH), a condition characterised by profound structural remodelling of pulmonary arteries and arterioles. Methods and results HDAC1 and HDAC5 protein levels were elevated in lungs from human idiopathic PAH and in lungs and right ventricles from rats exposed to hypoxia. Immunohistochemistry localised increased expression to remodelled vessels in the lung. Both valproic acid (VPA), a class I HDAC inhibitor, and suberoylanilide hydroxamic acid (SAHA), an inhibitor of class I, II and IV HDACs, mitigated the development and reduced established hypoxia-induced pulmonary hypertension in the rat. Both VPA and SAHA inhibited the “imprinted” highly proliferative phenotype of fibroblasts and R-cells from pulmonary hypertensive bovine vessels and PDGF-stimulated growth of human vascular smooth muscle cells in culture. Exposure to VPA and SAHA was associated with increased levels of p21and FOXO3 and reduced expression of survivin. The significantly higher level of expression of cKIT, MCP-1, IL-6, SDF-1, PDGFb and S100A4 in the R-cells were down regulated by VPA and SAHA treatment. Conclusions Increased HDAC activity contributes to the vascular pathology of pulmonary hypertension. The effectiveness of HDAC inhibitors VPA and SAHA, in models of PAH, support a therapeutic strategy based on HDAC inhibition in PAH.

Emerging Roles for Histone Deacetylases in Pulmonary Hypertension and Right Ventricular Remodeling (2013 Grover Conference series)

“…Together with Zhao and colleagues, 80,81 we showed that VPA and the pan-HDAC inhibitor, SAHA, can reverse existing PH and RV hypertrophy in male SD rats exposed to normobaric hypoxia. Rats were housed under hypoxic conditions for 2 weeks before HDAC inhibitor treatment, via drinking water, for 2 additional weeks; immunoblotting confirmed that HDAC inhibitor treatment increased histone acetylation in the lungs.…”

“…79 Consistent with this, in a separate study, both SAHA and VPA were shown to stimulate the p21 CDK in lungs of chronically hypoxic rats, and this was associated with reduced pulmonary arteriolar muscularization. 80 HDAC inhibitors also reduced expression of the antiapoptotic protein BCL-2 in these rats, which suggests that HDAC inhibition blocks pulmonary vascular remodeling by concomitantly suppressing cell proliferation and promoting cell death.…”

“…We found that class I HDAC expression and activity are dramatically elevated in PH fibroblasts and R cells, and selective class I HDAC inhibitors (VPA and apicidin) block the ability of both cell types to proliferate. 80,82 Once again, the antiproliferative action of class I HDAC inhibitors in PH fibroblasts and R cells was associated with induction of FoxO3a and p21. Importantly, HDAC inhibitors were able to block pulmonary vascular cell proliferation at doses that did not alter cell viability.…”

Angiogenesis and Cardiovascular Diseases: The Emerging Role of HDACs

“…Elevated levels of HDAC1 and HDAC5 have been observed in the PAH lungs, and treatments with HDACi such as SAHA and VPA reduce disease worsening in rat models of pulmonary hypertension [105]. In addition, MEF2 might have a protective role in PAH progression as the expression of MEF2 and its transcriptional targets are signiicantly decreased in pulmo-nary artery ECs from patients with PAH.…”

Hypoxia and Pulmonary Hypertension

“…Zinc-binding motifs have been considered as potential PH drug-therapeutic targets with phosphodiesterase type 5 (PDE5) and histone deacetylases as examples [54,55]. Zinc is a structural component of a number of intracellular enzymes, transcription factors, other proteins and cofactors and is a putative drug target for PH.…”