HDAC6: A Novel Histone Deacetylase Implicated in Pulmonary Arterial Hypertension

Olivier Boucherat,Valérie Nadeau,François Potus,Sandra Breuils-Bonnet,Roxane Paulin,Alice Bourgeois,Sébastien Bonnet,Caroline Lambert,Sophie Chabot,Marie-Claude Lampron,Renée Paradis,Isabelle Trinh,Steeve Provencher,Elena A Goncharova

doi:10.1038/s41598-017-04874-4

Abstract

Pulmonary arterial hypertension (PAH) is a vascular remodeling disease with limited therapeutic options. Although exposed to stressful conditions, pulmonary artery (PA) smooth muscle cells (PASMCs) exhibit a “cancer-like” pro-proliferative and anti-apoptotic phenotype. HDAC6 is a cytoplasmic histone deacetylase regulating multiple pro-survival mechanisms and overexpressed in response to stress in cancer cells. Due to the similarities between cancer and PAH, we hypothesized that HDAC6 expression is increased in PAH-PASMCs to face stress allowing them to survive and proliferate, thus contributing to vascular remodeling in PAH. We found that HDAC6 is significantly up-regulated in lungs, distal PAs, and isolated PASMCs from PAH patients and animal models. Inhibition of HDAC6 reduced PAH-PASMC proliferation and resistance to apoptosis in vitro sparing control cells. Mechanistically, we demonstrated that HDAC6 maintains Ku70 in a hypoacetylated state, blocking the translocation of Bax to mitochondria and preventing apoptosis. In vivo, pharmacological inhibition of HDAC6 improved established PAH in two experimental models and can be safely given in combination with currently approved PAH therapies. Moreover, Hdac6 deficient mice were partially protected against chronic hypoxia-induced pulmonary hypertension. Our study shows for the first time that HDAC6 is implicated in PAH development and represents a new promising target to improve PAH.

Highlights

Pulmonary arterial hypertension (PAH) is a complex and multifactorial disease characterized by a progressive elevation of pulmonary vascular resistance, due to a cancer-like proliferative and apoptosis-resistant phenotype of pulmonary artery (PA) cells including smooth muscle cells (PASMCs) and endothelial cells (PAECs)[1]
We noted that immunoreactivity for histone deacetylase 6 (HDAC6) was considerably stronger in the lungs from PAH patients compared to the control lungs with a marked increase in PASMCs from the remodeled distal pulmonary arteries, as observed by the high degree of overlap between these two staining patterns (Fig. 1B)
In addition to PAH-PASMCs, HDAC6 was overexpressed in PAH-PAECs and PAH-right ventricular (RV) as well as in the RV of rats exposed to Su/Hx and MCT (Supplementary Figure S1 and S2)

Summary

Introduction

Pulmonary arterial hypertension (PAH) is a complex and multifactorial disease characterized by a progressive elevation of pulmonary vascular resistance, due to a cancer-like proliferative and apoptosis-resistant phenotype of pulmonary artery (PA) cells including smooth muscle cells (PASMCs) and endothelial cells (PAECs)[1]. To further substantiate our findings, we analyzed the expression level of HDAC6 in primary cultured human PAH-PASMCs. In agreement with the above results, HDAC6 protein expression but not mRNA was robustly increased in PAH-PASMCs compared to control cells (Fig. 1A and Supplementary Figure S1).

Results

Conclusion