Functional Changes in Pulmonary Arterial Endothelial Cells Associated with BMPR2 Mutations |
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| Authors: | Hu Wang Ruirui Ji Jie Meng Qiqiong Cui Wenxin Zou Lei Li Guoliang Wang Li Sun Zhaohui Li Lei Huo Yuxin Fan Daniel J Penny |
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| Institution: | 1. Section of Cardiology, Department of Pediatrics, Texas Children''s Hospital, Baylor College of Medicine, Houston, Texas, United States of America.; 2. Cardiovascular Clinical Research Core, Texas Children''s Hospital, Baylor College of Medicine, Houston, Texas, United States of America.; 3. Department of Pathology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, United States of America.; Chinese Academy of Medical Sciences, China, |
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| 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. |
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