Tipifarnib prevents development of hypoxia-induced pulmonary hypertension

Cardiovasc Res. 2017 Mar 1;113(3):276-287. doi: 10.1093/cvr/cvw258.

Abstract

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.

Keywords: Endothelium; Farnesylation; Pulmonary hypertension; Rho.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antihypertensive Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Disease Models, Animal
  • Endothelial Cells / drug effects
  • Endothelial Cells / enzymology
  • Endothelial Cells / pathology
  • Enzyme Inhibitors / pharmacology*
  • Farnesyltranstransferase / antagonists & inhibitors*
  • Farnesyltranstransferase / metabolism
  • Humans
  • Hypertension, Pulmonary / enzymology
  • Hypertension, Pulmonary / etiology
  • Hypertension, Pulmonary / prevention & control*
  • Hypoxia / complications
  • Hypoxia / drug therapy*
  • Hypoxia / enzymology
  • Male
  • Mice, Inbred C57BL
  • Phenotype
  • Protein Prenylation
  • Proteomics / methods
  • Pulmonary Artery / drug effects*
  • Pulmonary Artery / enzymology
  • Pulmonary Artery / pathology
  • Pulmonary Artery / physiopathology
  • Quinolones / pharmacology*
  • Time Factors
  • Transfection
  • Vasoconstriction / drug effects
  • Vasodilation / drug effects
  • rhoB GTP-Binding Protein / genetics
  • rhoB GTP-Binding Protein / metabolism

Substances

  • Antihypertensive Agents
  • Enzyme Inhibitors
  • Quinolones
  • Farnesyltranstransferase
  • rhoB GTP-Binding Protein
  • tipifarnib