Unknown,Transcriptomics,Genomics,Proteomics

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Acquired chromosome abnormalities in the lungs of patients with Pulmonary Arterial Hypertension (Illumina)

ABSTRACT: Vascular remodeling in pulmonary arterial hypertension (PAH) involves proliferation and migration of endothelial and smooth muscle cells, leading to obliterative vascular lesions. Previous studies have indicated that the endothelial cell proliferation is quasi-neoplastic, with evidence of monoclonality and instability of short DNA microsatellite sequences. To assess whether there is larger scale genomic instability, we performed genome-wide microarray copy number analysis on pulmonary artery endothelial (PAEC) and smooth muscle cells isolated from the lungs of PAH patients. Mosaic chromosomal abnormalities were detected in five of nine PAEC cultures from PAH lungs and zero of four controls. Fluorescent in situ hybridization analysis confirmed the presence of these abnormalities in vivo in two of three cases. One patient harbored a germline mutation of BMPR2, the primary genetic cause of PAH, and a somatic loss of chromosome-13, which constitutes a second hit in the same pathway by deleting Smad-8. In two female cases with mosaic loss of the X-chromosome, methylation analysis showed that the active X was deleted. Remarkably, one also showed completely skewed X-inactivation in the non-deleted cells, suggesting the PAEC population was clonal prior to the acquisition of the chromosome abnormality. Our data indicate a high frequency of genetically abnormal sub-clones within the lung vessels of patients with PAH and provide the first definitive evidence of a second genetic hit in a patient with a germline BMPR2 mutation. We propose that these chromosome abnormalities may confer a growth advantage and thus contribute to the progression of PAH. Cross-sectional study of genomic copy number in cells cultured from the lungs of PAH patients.

ORGANISM(S): Homo sapiens

SUBMITTER: Christopher Coldren

PROVIDER: E-GEOD-21097 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Somatic chromosome abnormalities in the lungs of patients with pulmonary arterial hypertension.

Aldred Micheala A MA Comhair Suzy A SA Varella-Garcia Marileila M Asosingh Kewal K Xu Weiling W Noon George P GP Thistlethwaite Patricia A PA Tuder Rubin M RM Erzurum Serpil C SC Geraci Mark W MW Coldren Christopher D CD

American journal of respiratory and critical care medicine 20100625 9

<h4>Rationale</h4>Vascular remodeling in pulmonary arterial hypertension (PAH) involves proliferation and migration of endothelial and smooth muscle cells, leading to obliterative vascular lesions. Previous studies have indicated that the endothelial cell proliferation is quasineoplastic, with evidence of monoclonality and instability of short DNA microsatellite sequences.<h4>Objectives</h4>To assess whether there is larger-scale genomic instability.<h4>Methods</h4>We performed genome-wide micro ...[more]

PMID: 20581168

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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

Acquired chromosome abnormalities in the lungs of patients with Pulmonary Arterial Hypertension (Illumina)

Publications

Somatic chromosome abnormalities in the lungs of patients with pulmonary arterial hypertension.

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