Abstract 230: Protein Farnesylation Inhibitor Tipifarnib Prevents Development of Chronic Hypoxia-induced Pulmonary Hypertension

Study objectives: Small GTPase RhoB contributes to pulmonary vascular remodelling in pulmonary hypertension. Farnesylation of RhoB augments cell proliferation while geranylgeranylation of RhoB is believed to be pro-apoptotic. We hypothesized that farnesyltransferase inhibitors may prevent vascular pathology in pulmonary hypertension. We studied the effects of farnesyltransferase inhibitor Tipifarnib on pulmonary vascular remodelling and vasoreactivity in chronically hypoxic pulmonary hypertensive mice and cultured human pulmonary artery endothelial cells (HPAECs). Chemical proteomics was used to characterise Tipifarnib-induced changes in protein prenylation while label- free quantitative proteomics was used to characterise changes induced by overexpression of RhoB prenylation mutants: farnesylated-only or geranlygeranylated-only RhoB in HPAECs. The effects of Tipifarnib on Ras and Rho GTPases expression and activity, filamentous and globular actin levels and eNOS pathway, were also studied. Results: Oral ...