期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 121, 期 9, 页码 3735-3746出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI43382
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资金
- Sigrid Juselius Foundation
- Instrumentarium Foundation
- Finnish Foundation for Cardiovascular Research
- Finnish Cultural Foundation
- Finnish Foundation for Pediatric Research
- Academy of Finland
- Department of Pediatrics of Mie University Graduate School of Medicine, Japan
- Scleroderma Research Foundation
- Howard Hughes Medical Institute
- National Institutes of Health (NHLBI) [R01-HL087118, HL58115, HL64937]
- CMREF-PHBI [UL1RR024986]
- Dwight and Vera Dunlevie Endowed Professorship
- Grants-in-Aid for Scientific Research [23591565] Funding Source: KAKEN
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 PPAR gamma and beta-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 PPAR gamma/beta-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 PPAR gamma 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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