Abstract 12771: HDAC Inhibition With Quisinostat Reduces Pulmonary Vascular Remodeling in Experimentally Induced Pulmonary Arterial Hypertension

Abstract

Introduction: Histone deacetylases (HDACs) expression and activity are increased in pulmonary arterial hypertension (PAH). Although inhibiting HDACs has been promoted as a treatment for PAH, results from preclinical studies were equivocal and raised concerns regarding safety. Quisinostat is a “second generation” HDAC inhibitor, which is highly potent against HDAC1 and elicits a prolonged pharmacodynamic response. Hypothesis: Quisinostat may exert therapeutic effects in experimentally-induced PAH. Methods: HDAC1 expression was measured in lungs and microvascular endothelial cells (MVECs) from control donors and PAH patients. HDAC activity, proliferation and inflammation were measured after quisinostat treatment of PAH MVECs. Chronic quisinostat treatment was tested in three PAH rat models: the Sugen + hypoxia (SuHx), the Monocrotaline shunt flow (MF) and pulmonary artery banding (PAB) model. Results: HDAC1 expression is increased in lungs of PAH patients. Quisinostat decreased proliferation and mitigated inflammatory cytokine expression in MVECs. Conditioned medium from quisinostat treated PAH MVECs inhibited the growth of healthy pulmonary artery smooth muscle cells. In vivo , quisinostat treatment reduced right ventricular (RV) systolic pressure, RV afterload and total pulmonary resistance in SuHx rats. Further analysis by histology revealed that quisinostat reduced pulmonary vascular remodeling in both SuHx and MF rat models by reducing proliferation and perivascular inflammation. The PAB rat model demonstrated that quisinostat had no independent effect on RV function or remodeling. Conclusions: Quisinostat can partly reverse RV afterload and pulmonary vascular remodeling in established experimental PAH and may be a promising intervention for PAH.