Tipifarnib prevents development of hypoxia-induced pulmonary hypertension

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.

miR-190a-5p participates in the regulation of hypoxia-induced pulmonary hypertension by targeting KLF15 and can serve as a biomarker of diagnosis and prognosis in chronic obstructive pulmonary disease complicated with pulmonary hypertension

“… 37 , 38 However, several studies have indicated that the gene expression, protein content, and activity of lung eNOS are high in mice with chronic hypoxic PH. 39 – 41 These findings are consistent with our observations. Nitric oxide (NO) is a potent pulmonary artery vasodilator; altered NO production may contribute to the development of PH.…”

Mechanisms contributing to persistently activated cell phenotypes in pulmonary hypertension

“…That increased expression of growth factors such as platelet‐derived growth factor (PDGF), EGFR ligands, and transforming growth factor β (TGF‐β) are important in initiating development of PH is evidenced by the studies demonstrating that the inhibitor of the EGFR/PDGF receptor downstream effector RAS/RHOB, Tipifarnib (Duluc et al . ), the TGF‐β ligand trap, a soluble TGF‐β type II receptor extracellular domain expressed as an immunoglobulin‐Fc fusion protein (TGFBRII‐Fc) (Yung et al . ) and direct PDGF inhibition with the tyrosine kinase inhibitor Imatinib (Pullamsetti et al .…”

Insights on the epigenetic mechanisms underlying pulmonary arterial hypertension

“…Mechanistically, it has been proposed that miR-223 overexpression could inhibit key regulators of actin dynamics and cell proliferation, such as myosin phosphatase (MYPT1) and RhoB, attenuating vascular remodeling and PAH ( 67 ). In agreement with this, recent studies have demonstrated that inhibition of the Rho family protein with the selective Rho inhibitors tipifarnib or fasudil is capable of attenuating ventricular remodeling ( 83 ) and preventing development of hypoxia-induced PAH ( 84 ).…”