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BibTex format

author = {Duluc, L and Ahmetaj-Shala, B and Mitchell, J and Abdul, Salam VB and Mahomed, AS and Aldabbous, L and Oliver, E and Iannone, L and Dubois, OD and Storck, EM and Tate, EW and Zhao, L and Wilkins, MR and Wojciak-Stothard, B},
doi = {cvr/cvw258},
journal = {Cardiovascular Research},
pages = {276--287},
title = {Tipifarnib prevents development of hypoxia-induced pulmonary hypertension},
url = {},
volume = {113},
year = {2017}

RIS format (EndNote, RefMan)

AB - Aims.RhoB plays a key role in the pathogenesis of hypoxia-induced pulmonary hypertension. Farnesylated RhoB promotes growth responses in cancer cells and we investigated whether inhibition of protein farnesylation will have a protective effect. Methods and Results.The analysis of lung tissues from rodent models and pulmonary hypertensive patientsshowed increased levels of protein farnesylation. Oral farnesyltransferase inhibitor tipifarnib prevented development of hypoxia-induced pulmonary hypertension in mice. Tipifarnib reduced hypoxia-induced vascular cell proliferation, increased endothelium-dependent vasodilatation and reduced vasoconstriction of intrapulmonary arteries without affecting cell viability. Protective effects of tipifarnib were associated with inhibition of Ras and RhoB, actin depolymerisation and increased eNOS expression in vitroand in vivo. Farnesylated-only RhoB (F-RhoB) increased proliferative responses in cultured pulmonary vascular cells, mimicking the effects of hypoxia, while both geranylgeranylated-only RhoB (GG-RhoB) and tipifarnib had an inhibitory effect. Label-free proteomics linked F-RhoB with cell survival, activation of cell cycle and mitochondrial biogenesis. Hypoxia increased and tipifarnib reduced the levels of F-RhoB-regulated proteins in the lung, reinforcing the importance of RhoB as a signalling mediator.Unlike simvastatin, tipifarnib did not increase the expression levels of Rho proteins.Conclusions.Our study demonstrates the importance of protein farnesylation in pulmonary vascular remodeling and provides a rationale for selective targeting of this pathway in pulmonary hypertension.
AU - Duluc,L
AU - Ahmetaj-Shala,B
AU - Mitchell,J
AU - Abdul,Salam VB
AU - Mahomed,AS
AU - Aldabbous,L
AU - Oliver,E
AU - Iannone,L
AU - Dubois,OD
AU - Storck,EM
AU - Tate,EW
AU - Zhao,L
AU - Wilkins,MR
AU - Wojciak-Stothard,B
DO - cvr/cvw258
EP - 287
PY - 2017///
SN - 1755-3245
SP - 276
TI - Tipifarnib prevents development of hypoxia-induced pulmonary hypertension
T2 - Cardiovascular Research
UR -
VL - 113
ER -