TY - JOUR
T1 - Pk10453, a nonselective platelet-derived growth factor receptor inhibitor, prevents the progression of pulmonary arterial hypertension
AU - Medarametla, Venkatrao
AU - Festin, Stephen
AU - Sugarragchaa, Chuluunbaatar
AU - Eng, Alexander
AU - Naqwi, Amir
AU - Wiedmann, Timothy
AU - Zisman, Lawrence S.
N1 - Publisher Copyright:
© 2014 by the Pulmonary Vascular Research Institute. All rights reserved.
PY - 2014/3/1
Y1 - 2014/3/1
N2 - The platelet-derived growth factor (PDGF) signaling pathway has been found to be activated in human pulmonary arterial hypertension (PAH) and in animal models of the disease. Our study tested the hypothesis that a novel, nonselective inhaled PDGF receptor inhibitor, PK10453, would decrease pulmonary hypertension both in the rat monocrotaline (MCT) model and the rat MCT plus pneumonectomy (MCT+PN) model of PAH. PK10453, delivered by inhalation for 4 (D4)- and 8 (D8)-minute exposures 3 times a day for 2 weeks, decreased right ventricular systolic pressure (RVSP) in both the rat MCT and rat MCT+PN models: RVSP was 80.4±2.6 mmHg in the vehicle MCT group (n=6), 44.4±5.8 mmHg in the D4 MCT group (n=6), and 37.1±4.5 mmHg in the D8 MCT group (n=5; P < 0.001 vs. vehicle); RVSP was 75.7±7.1 mmHg in the vehicle MCT+PN group (n=9), 40.4±2.7 mmHg in the D4 MCT+PN group (n=10), and 43.0±3.0 mmHg in the D8 MCT+PN group (n=8; P < 0.001). In the rat MCT+PN model, continuous telemetry monitoring of pulmonary artery pressures also demonstrated that PK10453 prevented the progression of PAH. Imatinib given by inhalation was equally effective in the MCT model but was not effective in the MCT+PN model. Immunohistochemistry demonstrated increased activation of the PDGF β receptor compared to the PDGFα receptor in neointimal and perivascular lesions found in the MCT+PN model. We show that imatinib is selective for the PDGF α receptor, whereas PK10453 has a lower half-maximal inhibitor concentration (IC50) for inhibition of kinase activity of both the PDGF α and PDGFβ receptors compared to imatinib. In conclusion, PK10453, when delivered by inhalation, significantly decreased the progression of PAH in the rat MCT and MCT+PN models. Nonselective inhibition of both the PDGF α and PDGF β r ceptors may have a therapeutic advantage over selective PDGF α receptor inhibition in PAH.
AB - The platelet-derived growth factor (PDGF) signaling pathway has been found to be activated in human pulmonary arterial hypertension (PAH) and in animal models of the disease. Our study tested the hypothesis that a novel, nonselective inhaled PDGF receptor inhibitor, PK10453, would decrease pulmonary hypertension both in the rat monocrotaline (MCT) model and the rat MCT plus pneumonectomy (MCT+PN) model of PAH. PK10453, delivered by inhalation for 4 (D4)- and 8 (D8)-minute exposures 3 times a day for 2 weeks, decreased right ventricular systolic pressure (RVSP) in both the rat MCT and rat MCT+PN models: RVSP was 80.4±2.6 mmHg in the vehicle MCT group (n=6), 44.4±5.8 mmHg in the D4 MCT group (n=6), and 37.1±4.5 mmHg in the D8 MCT group (n=5; P < 0.001 vs. vehicle); RVSP was 75.7±7.1 mmHg in the vehicle MCT+PN group (n=9), 40.4±2.7 mmHg in the D4 MCT+PN group (n=10), and 43.0±3.0 mmHg in the D8 MCT+PN group (n=8; P < 0.001). In the rat MCT+PN model, continuous telemetry monitoring of pulmonary artery pressures also demonstrated that PK10453 prevented the progression of PAH. Imatinib given by inhalation was equally effective in the MCT model but was not effective in the MCT+PN model. Immunohistochemistry demonstrated increased activation of the PDGF β receptor compared to the PDGFα receptor in neointimal and perivascular lesions found in the MCT+PN model. We show that imatinib is selective for the PDGF α receptor, whereas PK10453 has a lower half-maximal inhibitor concentration (IC50) for inhibition of kinase activity of both the PDGF α and PDGFβ receptors compared to imatinib. In conclusion, PK10453, when delivered by inhalation, significantly decreased the progression of PAH in the rat MCT and MCT+PN models. Nonselective inhibition of both the PDGF α and PDGF β r ceptors may have a therapeutic advantage over selective PDGF α receptor inhibition in PAH.
KW - Kinase inhibitors
KW - Platelet-derived growth factor (PDGF)
KW - Pulmonary arterial hypertension
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U2 - 10.1086/674881
DO - 10.1086/674881
M3 - Article
AN - SCOPUS:85026339926
SN - 2045-8932
VL - 4
SP - 82
EP - 102
JO - Pulmonary Circulation
JF - Pulmonary Circulation
IS - 1
ER -