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Disruption of PPARγ/β-catenin–mediated regulation of apelin impairs BMP-induced mouse and human pulmonary arterial EC survival
Tero-Pekka Alastalo, … , Howard Y. Chang, Marlene Rabinovitch
Tero-Pekka Alastalo, … , Howard Y. Chang, Marlene Rabinovitch
Published August 8, 2011
Citation Information: J Clin Invest. 2011;121(9):3735-3746. https://doi.org/10.1172/JCI43382.
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Research Article Pulmonology

Disruption of PPARγ/β-catenin–mediated regulation of apelin impairs BMP-induced mouse and human pulmonary arterial EC survival

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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

Tero-Pekka Alastalo, Molong Li, Vinicio de Jesus Perez, David Pham, Hirofumi Sawada, Jordon K. Wang, Minna Koskenvuo, Lingli Wang, Bruce A. Freeman, Howard Y. Chang, Marlene Rabinovitch

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Figure 9

Apelin replacement reverses PAH in TIE2CrePPARγfl/fl mice.

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Apelin replacement reverses PAH in TIE2CrePPARγfl/fl mice.
   
(A) RV sy...
(A) RV systolic pressure (RVSP) measurement of WT or TIE2CrePPARγfl/fl mice treated with PBS vehicle control or apelin (200 μg/kg). (B) RV mass, measured as a ratio of the RV to that of the LV plus septum (RV/LV+S). (C) Muscularization of alveolar wall arteries is shown as a percentage of muscularized arteries from all 15- to 50-μm-diameter arteries. Bars represent mean ± SEM from 7 (A and B) or 5 (C) animals per group. (D) Representative anti–αSMC-actin (Actin) and Movat pentachrome–stained sections of pulmonary arteries, demonstrating reduced muscularization of pulmonary arteries in apelin-treated TIE2CrePPARγfl/fl mice. Scale bar: 50 μm. Original magnification, ×400. **P < 0.01, ***P < 0.001 vs. WT control, #P < 0.05, ###P < 0.001 vs. untreated TIE2CrePPARγfl/fl control, 1-way ANOVA with Bonferroni multiple comparison test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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