title: Functional changes in pulmonary arterial endothelial cells associated with BMPR2 mutations.
abstract: Pulmonary arterial hypertension (PAH) is a devastating disease characterized by abnormal remodeling of small, peripheral pulmonary arteries. Germline mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene are a major risk factor for developing PAH. At present, the correlation between the BMPR2 mutation and the patient's prognosis remains controversial despite several investigations. In this study, we explored the functional effects of four BMPR2 mutations to dissect the functional significance of the BMPR2 gene defect. Cellular immunofluorescence assay of four mutants (Tyr67Cys, Thr268fs, Ser863Asn, and Gln433X) revealed that the BMPR2 protein containing Thr268fs, Ser863Asn, or Gln433X exhibited abnormal subcellular localization. The BrdU incorporation and TUNEL assay suggested that any of the BMPR2 mutations Thr268fs, Ser863Asn, or Gln433X could improve endothelial cell apoptosis and decrease cell proliferation. All of the four mutants could inhibit nitric oxide (NO) synthesis in HLMVE cells, and ET-1 levels increased in the cells transfected with mutant Ser863Asn. Our results will improve the understanding of the genotype-phenotype correlations and mechanisms associated with BMPR2 mutations.
authors.affiliation: Section of Cardiology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Hu
authors.initials: H
authors.lastname: Wang
authors.affiliation: Section of Cardiology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Ruirui
authors.initials: R
authors.lastname: Ji
authors.affiliation: Section of Cardiology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Jie
authors.initials: J
authors.lastname: Meng
authors.affiliation: Cardiovascular Clinical Research Core, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Qiqiong
authors.initials: Q
authors.lastname: Cui
authors.affiliation: Section of Cardiology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Zou
authors.affiliation: Section of Cardiology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Section of Cardiology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Pathology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.affiliation: Section of Cardiology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pathology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Lei
authors.initials: L
authors.lastname: Huo
authors.affiliation: Section of Cardiology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Section of Cardiology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Penny
mesh_terms: D017209:Apoptosis / Q000235:genetics; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism* / Q000648:ultrastructure; D019332:Endothelin-1 / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D020287:In Situ Nick-End Labeling; D008168:Lung / Q000378:metabolism / Q000648:ultrastructure; D009154:Mutation; D009569:Nitric Oxide / Q000096:biosynthesis; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
chemical_list: D019332:Endothelin-1; D009569:Nitric Oxide; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II