Reduced bone morphogenetic protein receptor 2 (BMPR2) expression in patients with pulmonary arterial hypertension (PAH) can impair pulmonary arterial EC (PAEC) function. This can adversely affect EC survival and promote SMC proliferation. We hypothesized that interventions to normalize expression of genes that are targets of BMPR2 signaling could restore PAEC function and prevent or reverse PAH. Here we have characterized, in human PAECs, a BMPR2-mediated transcriptional complex between PPARγ and β-catenin and shown that disruption of this complex impaired BMP-mediated PAEC survival. Using whole genome-wide ChIP-Chip promoter analysis and gene expression microarrays, we delineated PPARγ/β-catenin-dependent transcription of target genes including APLN, which encodes apelin. We documented reduced PAEC expression of apelin in PAH patients versus controls. In cell culture experiments, we showed that apelin-deficient PAECs were prone to apoptosis and promoted pulmonary arterial SMC (PASMC) proliferation. Conversely, we established that apelin, like BMPR2 ligands, suppressed proliferation and induced apoptosis of PASMCs. Consistent with these functions, administration of apelin reversed PAH in mice with reduced production of apelin resulting from deletion of PPARγ in ECs. Taken together, our findings suggest that apelin could be effective in treating PAH by rescuing BMPR2 and PAEC dysfunction.
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http://dx.doi.org/10.1172/JCI43382 | DOI Listing |
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Department of Medical Imaging, National Taiwan University Hospital, Taipei, Taiwan; Department of Medical Imaging, National Taiwan University Cancer Center, Taipei, Taiwan.
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Department of Medicine, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8558, USA; Department of Pediatrics, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8558, USA. Electronic address:
Pulmonary vascular diseases, particularly when accompanied by pulmonary hypertension, are complex disorders often requiring multimodal imaging for diagnosis and monitoring. Echocardiography is the primary screening tool for pulmonary hypertension, while cardiac MR imaging (CMR) is used for more detailed characterization and risk stratification in right ventricular failure. Chest computed tomography (CT) is used to detect vascular anomalies and parenchymal lung diseases.
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