Dataset Information

Hypoxia induces unique proliferative response in adventitial fibroblasts by activating PDGF? receptor-JNK1 signalling.

ABSTRACT:

Aims

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 ? receptor (PDGF?-R) signalling is associated with PH, we tested the hypothesis that the activation of PDGF?-R contributes to fibroblast proliferation and adventitial remodelling in PH.

Methods and 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. PDGF?-R phosphorylation was markedly elevated in PA adventitia of Neo-PH calves as well as in cultured PA fibroblasts isolated from Neo-PH animals. PDGF?-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 PDGF?-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 PDGF?-R-JNK1 axis to confer distinctively heightened proliferation and adventitial remodelling in PH.

SUBMITTER: Panzhinskiy E

PROVIDER: S-EPMC3400360 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Hypoxia induces unique proliferative response in adventitial fibroblasts by activating PDGFβ receptor-JNK1 signalling.

Panzhinskiy Evgeniy E Zawada W Michael WM Stenmark Kurt R KR Das Mita M

Cardiovascular research 20120626 3

<h4>Aims</h4>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 ...[more]

PMID: 22735370

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