Abstract
AimsRhoB 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 resultsThe 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.ConclusionsOur study demonstrates the importance of protein farnesylation in pulmonary vascular remodelling and provides a rationale for selective targeting of this pathway in pulmonary hypertension.
Highlights
Pulmonary hypertension (PH) is characterized by increased pulmonary vascular resistance due to pulmonary vasoconstriction and vascular remodelling and hypoxia is one of the major underlying causes of the disease.[1]Ras family of proteins, including Rho GTPases, are key regulators of actin dynamics and cell proliferation.[2]
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
We have recently shown that RhoB, a protein homologous to RhoA is required for hypoxia-induced HIF-1a stabilization, vascular cell proliferation, and migration in vitro.[4]
Summary
Pulmonary hypertension (PH) is characterized by increased pulmonary vascular resistance due to pulmonary vasoconstriction and vascular remodelling and hypoxia is one of the major underlying causes of the disease.[1]Ras family of proteins, including Rho GTPases, are key regulators of actin dynamics and cell proliferation.[2]. RhoB gene deletion attenuates PH in mice, indicating a unique role of this protein in the disease pathology.[4]
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