title: Tipifarnib prevents development of hypoxia-induced pulmonary hypertension.
abstract: 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.
  
  
  
  The analysis of lung tissues from rodent models and pulmonary hypertensive patients showed 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 depolymerization and increased eNOS expression in vitro and 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.
  
  
  
  Our study demonstrates the importance of protein farnesylation in pulmonary vascular remodelling and provides a rationale for selective targeting of this pathway in pulmonary hypertension.
authors.affiliation: Department of Medicine, Hammersmith Campus, Imperial College London, Du Cane Road, W120NN London, UK.
authors.forename: Lucie
authors.initials: L
authors.lastname: Duluc
authors.affiliation: National Heart and Lung Institute, Royal Brompton Campus, Imperial College London, Dovehouse Street, London SW3 6LY, UK.
authors.forename: Blerina
authors.initials: B
authors.lastname: Ahmetaj-Shala
authors.affiliation: National Heart and Lung Institute, Royal Brompton Campus, Imperial College London, Dovehouse Street, London SW3 6LY, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Mitchell
authors.affiliation: Department of Medicine, Hammersmith Campus, Imperial College London, Du Cane Road, W120NN London, UK.
authors.forename: Vahitha B
authors.initials: VB
authors.lastname: Abdul-Salam
authors.affiliation: Department of Medicine, Hammersmith Campus, Imperial College London, Du Cane Road, W120NN London, UK.
authors.forename: Abdul S
authors.initials: AS
authors.lastname: Mahomed
authors.affiliation: Department of Medicine, Hammersmith Campus, Imperial College London, Du Cane Road, W120NN London, UK.
authors.forename: Lulwah
authors.initials: L
authors.lastname: Aldabbous
authors.affiliation: Department of Medicine, Hammersmith Campus, Imperial College London, Du Cane Road, W120NN London, UK.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Oliver
authors.affiliation: Department of Medicine, Hammersmith Campus, Imperial College London, Du Cane Road, W120NN London, UK.
authors.forename: Lucio
authors.initials: L
authors.lastname: Iannone
authors.affiliation: Department of Medicine, Hammersmith Campus, Imperial College London, Du Cane Road, W120NN London, UK.
authors.forename: Olivier D
authors.initials: OD
authors.lastname: Dubois
authors.affiliation: Department of Medicine, Hammersmith Campus, Imperial College London, Du Cane Road, W120NN London, UK.|Department of Chemistry, South Kensington Campus, Imperial College London, Exhibition Road, London SW7 2AZ, UK.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Storck
authors.affiliation: Department of Chemistry, South Kensington Campus, Imperial College London, Exhibition Road, London SW7 2AZ, UK.
authors.forename: Edward W
authors.initials: EW
authors.lastname: Tate
authors.affiliation: Department of Medicine, Hammersmith Campus, Imperial College London, Du Cane Road, W120NN London, UK.
authors.forename: Lan
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Medicine, Hammersmith Campus, Imperial College London, Du Cane Road, W120NN London, UK.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Wilkins
authors.affiliation: Department of Medicine, Hammersmith Campus, Imperial College London, Du Cane Road, W120NN London, UK.
authors.forename: Beata
authors.initials: B
authors.lastname: Wojciak-Stothard
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D000860:Hypoxia / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D008810:Mice, Inbred C57BL; D010641:Phenotype; D017368:Protein Prenylation; D040901:Proteomics / Q000379:methods; D011651:Pulmonary Artery / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D015363:Quinolones / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D020743:rhoB GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D015363:Quinolones; D051231:Farnesyltranstransferase; D020743:rhoB GTP-Binding Protein; C402769:tipifarnib
keywords: Endothelium; Farnesylation; Pulmonary hypertension; Rho