Abstract 15215: Autophagy Inhibition Attenuate the Development and Progression of Pulmonary Hypertension

Abstract

Introduction: Autophagy plays an important role in the pathogenesis of pulmonary hypertension. However, the potential therapeutic benefit of autophagy inhibition remains undetermined. Hypothesis: ROC-325 was developed as a novel small molecule lysosomal autophagy inhibitor that has demonstrated significantly more potent anticancer activity than the antimalarial drug hydroxychloroquine (HCQ). Methods: Rats with monocrotaline-induced PH (MCT-PH) and hypoxia/Sugen-induced severe PH were treated with ROC-325 and the related effects on echocardiography, hemodynamics, right ventricle hypertrophy, and pulmonary vascular remodeling were assessed. Pulmonary arterial pressure (PAP) and isometric tension were measured in isolated perfused/ventilated mouse lungs and rat PA rings. The in vitro effects on ROC-325 on autophagy, proliferation, viability, apoptosis and endothelial nitric oxide (NO) synthase (eNOS)-NO signaling were tested in human and rat pulmonary artery smooth muscle cells (PASMCs) as well as human pulmonary artery endothelial cells (PAECs) and rat pulmonary microvascular endothelial cells (PMVECs). Results and Conclusions: The therapeutic benefits of a novel lysosomal autophagy inhibitor, ROC-325, in experimental pulmonary hypertension (PH) models. Specifically, ROC-325 treatment prevents the development of monocrotaline (MCT)-induced PH, right ventricular dysfunction, and pulmonary vascular remodeling, and reverses the progression of established MCT-PH. Meanwhile, ROC-325 treatment attenuates high K + or alveolar hypoxia-induced pulmonary vasoconstriction. Mechanistically, in PASMC and PAEC, ROC-325 inhibits autophagic pathways, reduces hypoxia induced-hypoxia inducible factor (HIF) accumulation and blocks endothelial nitric oxide (NO) synthase (eNOS)-NO signaling activation. These studies illustrate the discovery of ROC-325 as a novel promising agent for PH therapy.