Hypoxia induces unique proliferative response in adventitial fibroblasts by activating PDGFβ receptor-JNK1 signalling.
OBJECTIVE
Pulmonary hypertension (PH) is a devastating condition for which no disease-modifying therapies exist. PH is recognized as proliferative disease of the pulmonary artery (PA). In the experimental newborn calf model of hypoxia-induced PH, adventitial fibroblasts in the PA wall exhibit a heightened replication index. Because elevated platelet-derived growth factor β receptor (PDGFβ-R) signalling is associated with PH, we tested the hypothesis that the activation of PDGFβ-R contributes to fibroblast proliferation and adventitial remodelling in PH.


RESULTS
Newborn calves were exposed to either ambient air (P(B) = 640 mmHg) (Neo-C) or high altitude (P(B) = 445 mm Hg) (Neo-PH) for 2 weeks. PDGFβ-R phosphorylation was markedly elevated in PA adventitia of Neo-PH calves as well as in cultured PA fibroblasts isolated from Neo-PH animals. PDGFβ-R activation with PDGF-BB stimulated higher replication in Neo-PH cells compared with that of control fibroblasts. PDGF-BB-induced proliferation was dependent on reactive oxygen species generation and extracellular signal-regulated kinase1/2 activation in both cell populations; however, only Neo-PH cell division via PDGFβ-R activation displayed a unique dependence on c-Jun N-terminal kinase1 (JNK1) stimulation as the blockade of JNK1 with SP600125, a pharmacological antagonist of the JNK pathway, and JNK1-targeted siRNA selectively blunted Neo-PH cell proliferation.


CONCLUSIONS
Our data strongly suggest that hypoxia-induced modified cells engage the PDGFβ-R-JNK1 axis to confer distinctively heightened proliferation and adventitial remodelling in PH.
Department of Pharmaceutical Sciences,  University of Wyoming, Laramie, WY,  USA.
Evgeniy
E
Panzhinskiy
W Michael
WM
Zawada
Kurt R
KR
Stenmark
Mita
M
Das
D063194:Adventitia / Q000201:enzymology* / Q000473:pathology; D000531:Altitude; D000818:Animals; D000831:Animals, Newborn; D000077214:Becaplermin; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004789:Enzyme Activation; D065627:Familial Primary Pulmonary Hypertension; D005347:Fibroblasts / Q000201:enzymology* / Q000473:pathology; D006976:Hypertension, Pulmonary / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D000860:Hypoxia / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D011651:Pulmonary Artery / Q000201:enzymology* / Q000473:pathology; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection
D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D017382:Reactive Oxygen Species; D000077214:Becaplermin; D020797:Receptor, Platelet-Derived Growth Factor beta; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8