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Novel role of Pre‐B‐Cell Colony Enhancing Factor (PBEF) in pulmonary arterial hypertension (PAH)
Author(s) -
Machado Roberto F,
MorenoVinasco Liliana,
Chiang Eddie,
Zaidi Syed Rafe,
Sammani Saad,
Mirzapoiazova Tamara,
Toth Peter T.,
Ayetkin Meitin,
Dweik Raed A,
Archer Stephen L.,
Garcia Joe G.N
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.1023.6
Subject(s) - proinflammatory cytokine , apoptosis , medicine , downregulation and upregulation , biomarker , endocrinology , chemistry , inflammation , andrology , biochemistry , gene
The discovery of novel mediators in PAH allows for novel insights into PAH pathobiology and identification of therapeutic targets. PBMC expression profiles from 7 PAH patients (49±7 years, mPAP 55±18 mmHg, PVR 14±11 U) and 10 healthy controls (45±7 years) identified 224 differentially expressed genes including PBEF as an upregulated gene in PAH. We previously identified PBEF as a mediator in lung injury, with extracellular proinflammatory cytokine‐like activity and intracellular enzymatic activity regulating NAD levels, cell redox state, histone deacetylases and inhibiting apoptosis. Plasma PBEF levels were higher in PAH patients (n=10, 46±17 years, mPAP 56±18 mmHg, PVR 10±4 U) than controls (n=9, 33±7 years), (5000±2000 vs. 7500 ± 3000 pg/ml; P=0.04) and trended with BNP levels (R=0.6, P=0.08) and inversely with 6‐minute walk distance (R=−0.57, P=0.08). Immunohistochemistry in explanted PAH lungs (n=3) revealed significant PBEF expression in plexiform lesions and in remodeled PAs, without PBEF staining in PAs of controls. Finally, compared to WT control mice, PBEF heterozygous mice (PBEF+/−) developed less severe PH (FIO2=10% and SU5416 for 3 weeks) with less significant elevations in RVSP (PBEF+/+ 19 ± 2 vs. PBEF+/− 12 ± 4 mmHg, P=0.03) and less RVH (RV/LV+S: PBEF+/+ 0.44 ± 0.05 vs. PBEF+/− 0.34 ± 0.08, P=0.06). Our results implicate PBEF as a novel biomarker and therapeutic target in PAH.