Computational Drug Repurposing Identifies Lgals8 and Nherf1 as Regulators of Endothelial Metabolic Activation Relevant to Pulmonary Hypertension

Background u0026 Hypothesis: Pulmonary hypertension (PH) is a fatal and under-studied vascular disease. Owing to parallels in the pathogenesis of cancer and PH, application of knowledge aided network based analyses of cancer to PH may define novel pathogenic mechanisms and facilitate computational repurposing of chemotherapies for PH. Methods u0026 Results: RNA sequencing from u003e800 cancer cell lines exposed to 368 chemotherapies were combined with a novel computational algorithm, EDDY (Evaluating Differential DependencY), to define re-wiring of PH gene dependency networks responsible for chemosensitivity. For many drugs, rewiring of a specific PH gene cluster (cluster 15, C15) was observed in drug-resistant cells. The BET bromodomain inhibitor IBET762 was the top-ranked drug linked to C15. In human pulmonary arterial endothelial cells (PAECs), inflammatory IL-1β altered C15 expression with modulation of PH-relevant indices such as apoptosis, fibrosis, metabolism, and inflammation--all reversed by I-BET762. RNA kn...