title: Disruption of PPARγ/β-catenin-mediated regulation of apelin impairs BMP-induced mouse and human pulmonary arterial EC survival.
abstract: 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.
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305-5162, USA.
authors.forename: Tero-Pekka
authors.initials: TP
authors.lastname: Alastalo
authors.forename: Molong
authors.initials: M
authors.lastname: Li
authors.forename: Vinicio de Jesus
authors.initials: Vde J
authors.lastname: Perez
authors.forename: David
authors.initials: D
authors.lastname: Pham
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Sawada
authors.forename: Jordon K
authors.initials: JK
authors.lastname: Wang
authors.forename: Minna
authors.initials: M
authors.lastname: Koskenvuo
authors.forename: Lingli
authors.initials: L
authors.lastname: Wang
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Freeman
authors.forename: Howard Y
authors.initials: HY
authors.lastname: Chang
authors.forename: Marlene
authors.initials: M
authors.lastname: Rabinovitch
mesh_terms: D054392:Adipokines; D000818:Animals; D000073861:Apelin; D017209:Apoptosis / Q000502:physiology; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D046228:Microarray Analysis; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D011651:Pulmonary Artery / Q000166:cytology; D034741:RNA, Small Interfering / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C115436:APLN protein, human; D054392:Adipokines; D000073861:Apelin; C402826:Apln protein, mouse; D019485:Bone Morphogenetic Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047495:PPAR gamma; D034741:RNA, Small Interfering; D051176:beta Catenin; C498218:BMPR2 protein, human; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II