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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Cardiovasc+Res
2017 ; 113
(3
): 276-287
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Tipifarnib prevents development of hypoxia-induced pulmonary hypertension
#MMPMID28395021
Duluc L
; Ahmetaj-Shala B
; Mitchell J
; Abdul-Salam VB
; Mahomed AS
; Aldabbous L
; Oliver E
; Iannone L
; Dubois OD
; Storck EM
; Tate EW
; Zhao L
; Wilkins MR
; Wojciak-Stothard B
Cardiovasc Res
2017[Mar]; 113
(3
): 276-287
PMID28395021
show ga
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 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. CONCLUSIONS:
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.
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