Imatinib in pulmonary arterial hypertension: c-Kit inhibition

PVRI Member Authors: Raed A. Dweik, Franck Rahaghi, Paul Hassoun, Robert Frantz, Deborah Quinn


Pulmonary arterial hypertension (PAH) is a progressive disease characterized by severe remodeling of the pulmonary artery resulting in increased pulmonary artery pressure and right ventricular hypertrophy and, ultimately, failure. Bone marrow–derived progenitor cells play a critical role in vascular homeostasis and have been shown to be involved in the pathogenesis of PAH. A proliferation of c-Kit+ hematopoietic progenitors and mast cells has been noted in the remodeled vessels in PAH. Imatinib, a tyrosine kinase inhibitor that targets c-Kit, has been shown to be beneficial for patients with PAH. Here we hypothesize that the clinical benefit of imatinib in PAH could be related to c-Kit inhibition of progenitor cell mobilization and maturation into mast cells. As a corollary to the phase 3 study using imatinib in PAH, blood samples were collected from 12 patients prior to starting study drug (baseline) and while on treatment at weeks 4 and 24. Eight were randomized to imatinib and 4 to placebo. Circulating c-Kit+ and CD34+ CD133+hematopoietic progenitors as well as biomarkers of mast cell numbers and activation were measured. Circulating CD34+ CD133+ and c-Kit+ progenitor cells as well as c-Kit+/CD34+CD133+ decreased with imatinib therapy (all P < 0.05). In addition, total tryptase, a marker of mast cell load, dropped with imatinib therapy (P = 0.02) and was related to pulmonary vascular resistance (R = 0.7, P = 0.02). The findings support c-Kit inhibition as a potential mechanism of action of imatinib in PAH and suggest that tryptase is a potential biomarker of response to therapy.

Read the full article online


Cell Biochemistry and Metabolism, Differentiation and Proliferation, Structure and Function, interactions
Monocytes/ Macrophages/ Neutrophils/ Dendritic Cells/ Mast Cells
Pulmonary Hypertension
Pulmonary Vascular Remodeling


Samar Farha, Raed Dweik, Franck Rahaghi, Raymond Benza, Paul Hassoun, Robert Frantz, Fernando Torres, Deborah A. Quinn, Suzy Comhair, Serpil Erzurum, Kewal Asosingh

Published in:

Pulmonary Circulation Vol 4: No 3 cover image

August 2014

Pulmonary Circulation Vol 4: No 3

View this journal

Our research platform is the world.

Through worldwide collaboration, we can begin to answer the question of a global disease.

Join the PVRI