Aims.
RhoB plays a key role in the pathogenesis of hypoxia
-
induced pulmonary hypertension.
Farne
sylated 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 l
ung 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 depolymerisation and increased eNOS
expression
in vi
tro
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
-
fre
e 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 pa
thway in pulmonary hypertension.