A Potential Role for Exosomal Translationally Controlled Tumor Protein Export in Vascular Remodeling in Pulmonary Arterial Hypertension.
Stewart, Duncan J
American journal of respiratory cell and molecular biology
American Thoracic Society
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Ferrer, E., Dunmore, B., Hassan, D., Ormiston, M. L., Moore, S., Deighton, J., Long, L., et al. (2018). A Potential Role for Exosomal Translationally Controlled Tumor Protein Export in Vascular Remodeling in Pulmonary Arterial Hypertension.. American journal of respiratory cell and molecular biology, 59 (4), 467-478. https://doi.org/10.1165/rcmb.2017-0129oc
Pulmonary arterial hypertension (PAH) is characterized by increased proliferation and resistance to apoptosis of pulmonary vascular cells. Increased expression of translationally controlled tumor protein (TCTP), a pro-survival and anti-apoptotic mediator, has recently been demonstrated in patients with hereditary PAH (HPAH) although its role in the pathobiology of PAH remains unclear. Silencing of TCTP in blood outgrowth endothelial cells (BOECs) isolated from control subjects led to significant changes in morphology, cytoskeletal organization, increased apoptosis and decreased directionality during migration. As TCTP is also localized in extracellular vesicles (EVs), we isolated BOEC-derived EVs (exosomes and microparticles) by sequential ultracentrifugation. BOECs isolated from patients harboring BMPR2 mutations released more exosomes than controls in pro-apoptotic conditions. Furthermore, TCTP protein expression was significantly higher in exosomes compared to microparticles, indicating that TCTP is mainly exported via exosomes. Co-culture assays demonstrated that exosomes transferred TCTP from endothelial cells (ECs) to pulmonary artery smooth muscle cells (PASMCs) suggesting a role for endothelial-derived TCTP in conferring proliferation and apoptotic resistance. In an experimental model of PAH, rats treated with monocrotaline demonstrated increased concentrations of TCTP in the lung and plasma. Consistent with this finding, we observed increased circulating TCTP levels in patients with IPAH compared with controls. Therefore, our data suggests an important role for TCTP in regulating the critical vascular cell phenotypes implicated in the pathobiology of PAH. In addition, this research implicates TCTP as a potential biomarker for the onset and development of PAH.
Lung, Pulmonary Artery, Endothelial Cells, Myocytes, Smooth Muscle, Animals, Humans, Rats, Sprague-Dawley, Lentivirus, Hypertension, Pulmonary, Disease Models, Animal, Monocrotaline, Apoptosis, Cell Proliferation, Cell Movement, Cell Shape, Protein Transport, Mutation, Male, Bone Morphogenetic Protein Receptors, Type II, Exosomes, Vascular Remodeling, Biomarkers, Tumor
Dr. Ferrer was supported by the British Heart Foundation and SOCAP (Societat Catalana de Pneumologia). Drs. Dunmore and Ormiston were funded by the British Heart Foundation. This work was funded by awards to Professor Nick Morrell (British Heart Foundation Program Grant and the Fondation Leducq) and to Dr. Duncan Stewart (Canadian Institutes for Health Foundation Award). Infrastructure support was provided by the Cambridge National Institute for Health Research Biomedical Research Center.
British Heart Foundation (RG/13/4/30107)
External DOI: https://doi.org/10.1165/rcmb.2017-0129oc
This record's URL: https://www.repository.cam.ac.uk/handle/1810/278723