Selective inhibition of Histone deacetylases reverses vascular remodelling and improves right ventricle function in pulmonary hypertension

Abstract

Abstract Introduction Pulmonary arterial hypertension (PAH) is a progressive fatal disease characterized by abnormal remodelling of pulmonary vessels, leading to increased vascular resistance and right ventricle (RV) failure. This abnormal vascular remodelling is associated with endothelial cell dysfunction, increased proliferation of smooth muscle cells, inflammation, and disturbed transforming growth factor beta (TGF-β) signalling. Histone deacetylases (HDACs) have been shown to promote proliferation and inflammation in vascular cells. Although inhibition of HDACs using small molecule inhibitors attenuated vascular remodeling, these inhibitors worsened RV function in animal models of PAH. Therefore, we aim to validate Quisinostat, a selective inhibitor of HDACs whether it could reverse vascular remodeling in the lungs and improves RV function. Objective To determine the effect of Quisinostat on vascular remodelling and RV function in PAH. Methods and results We found that HDAC1 expression is increased in lungs of PAH patients. Inhibition of HDACs activity by Quisinostat significantly decreased TGF-β signaling and strongly decreased proliferation and inflammation in microvascular endothelial cells (MVECs). In addition, conditioned medium from Quisinostat treated PAH MVECs inhibited the growth of healthy smooth muscle cells. Quisinostat reversed abnormal vascular remodelling in the MCT-shunt and Sugen Hypoxia rat models of severe angioproliferative PAH, and improved RV function. Finally, Quisinostat improved the RV function in rats with RV pressure load induced by pulmonary artery banding. Importantly, Quisinostat exhibited no systemic and cardio toxic effects in vivo. Conclusions Our data demonstrate that selective inhibition of HDACs reverses vascular remodeling in the lungs and improves RV function. These data support the establishment of a clinical trial with Quisinostat in patients with PAH. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Dutch Lung Foundation