Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Investigation of endothelial cell gene dysregulation in early pulmonary arterial hypertension disease model

ABSTRACT: Endothelial cell (EC) dysfunction plays a key role in the pathogenesis of pulmonary arterial hypertension (PAH). To avoid cell cultures and whole lung tissue samples, we have, for the first time, used CD31 antibody coated magnetic beads in conjunction with genome scale RNA expression microarrays to profile ECs in vivo at any stage of PAH. We hypothesized that targeting early stages of the disease would identify novel mediators of PAH and genes linked to bone morphogenetic protein receptor 2 (BMPR2) signaling. Rats were treated with either monocrotaline (60mg/kg) or saline as control with 4 animals in each experimental group. Gene expression profiling was performed on primary pulmonary endothelial cells directly after isolation from whole lung tissue 5 days after treatment.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Molong Li

PROVIDER: E-GEOD-42767 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Loss of bone morphogenetic protein receptor 2 is associated with abnormal DNA repair in pulmonary arterial hypertension.

Li Molong M Vattulainen Sanna S Aho Joonas J Orcholski Marc M Rojas Vanessa V Yuan Ke K Helenius Mikko M Taimen Pekka P Myllykangas Samuel S De Jesus Perez Vinicio V Koskenvuo Juha W JW Alastalo Tero-Pekka TP

American journal of respiratory cell and molecular biology 20140601 6

Occlusive vasculopathy with intimal hyperplasia and plexogenic arteriopathy are severe histopathological changes characteristic of pulmonary arterial hypertension (PAH). Although a phenotypic switch in pulmonary endothelial cells (ECs) has been suggested to play a critical role in the formation of occlusive lesions, the pathobiology of this process is poorly understood. The goal of this study was to identify novel molecular mechanisms associated with EC dysfunction and PAH-associated bone morpho ...[more]

PMID: 24433082

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Project description:Bmpr2 mutations are critical risk factors for hereditary pulmonary arterial hypertension (hPAH) with approximately 20% of carriers developing disease. There is an unmet medical need to understand how environmental factors, such as inflammation, render Bmpr2 mutants susceptible to PAH. Overexpressing 5-lipoxygenase (5-LO) provokes lung inflammation and transient PAH in Bmpr2+/- mice. Accordingly, 5-LO and its metabolite, leukotriene B4 (LTB4), are candidates for the ‘second hit’. The purpose of this study was to determine how 5-LO-mediated pulmonary inflammation synergized with phenotypically-silent Bmpr2 defects to elicit significant pulmonary vascular disease in rats. Monoallelic Bmpr2 mutant rats were generated and found phenotypically normal for up to one year of observation. To evaluate whether a second hit would elicit disease, animals were exposed to 5-LO-expressing adenovirus (AdAlox5), monocrotaline, SU5416 or chronic hypoxia and analyzed. Bmpr2-mutant hPAH patient samples were assessed for neointimal 5-LO expression. Pulmonary artery endothelial cells (PAECs) were cultured with lentivirus expressing short hairpin RNA (shRNA) targeting Bmpr2 (shBmpr2) to model the impaired BMPR2 signaling, and were then exposed to 5-LO-expressing adenovirus (AdAlox5), and were assessed for phenotypic and transcriptomic changes. In vitro, BMPR2 deficiency, compounded by 5-LO-mediated inflammation, generated apoptosis-resistant and proliferative PAECs with mesenchymal characteristics. These transformed cells expressed nuclear envelop-localized 5-LO consistent with induced LTB4 production, as well as a transcriptomic signature similar to clinical disease, including upregulated NF-kB, IL-6 and TGF-β signaling pathways. The reversal of PAH and vasculopathy in Bmpr2 mutants by TGF-β antagonism suggests that TGF-β is critical for neointimal transformation. Thus, in a new two-hit model of disease, lung inflammation induced severe PAH pathology in Bmpr2+/- rats. Endothelial transformation required the activation of canonical and noncanonical TGF-β signaling pathways and was characterized by 5-LO nuclear envelope translocation with enhanced LTB4 production. This study offers one explanation of how an environmental injury unleashes the destructive potential of an otherwise-silent genetic mutation.

Dataset Information

Investigation of endothelial cell gene dysregulation in early pulmonary arterial hypertension disease model

Publications

Loss of bone morphogenetic protein receptor 2 is associated with abnormal DNA repair in pulmonary arterial hypertension.

Similar Datasets

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