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Citation

BibTex format

@article{Duluc:2017:cvr/cvw258,
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 = {http://dx.doi.org/10.1093/cvr/cvw258},
volume = {113},
year = {2017}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
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  - http://dx.doi.org/10.1093/cvr/cvw258
VL  - 113
ER  -
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Prof. Ed Tate
GSK Chair in Chemical Biology
Department of Chemistry
Molecular Sciences Research Hub, White City Campus,
82 Wood Lane, London, W12 0BZ

e.tate@imperial.ac.uk
Tel: +44 (0)20 759 + ext 43752 or 45821