Proteomic Analysis Implicates Translationally Controlled Tumor Protein as a Novel Mediator of Occlusive Vascular Remodeling in Pulmonary Arterial Hypertension
Background—Pulmonary arterial hypertension (PAH) is a lethal disease, characterized by excessive proliferation of pulmonary vascular endothelial cells (ECs). Hereditary PAH (HPAH) is often caused by mutations in the bone morphogenetic protein receptor type 2 gene (BMPR2). However, the mechanisms by which these mutations cause PAH remain unclear. Therefore, we screened for dysregulated proteins in blood-outgrowth ECs (BOECs) of HPAH patients with BMPR2 mutations compared with healthy controls.
Methods and Results—A total of 416 proteins were detected using two-dimensional polyacrylamide gel electrophoresis in combination with LC MS/MS analysis, of which 22 exhibited significantly altered abundance in BOECs from patients with HPAH. One of these proteins, translationally controlled tumor protein (TCTP), was selected for further study based on its well established role in promoting tumour cell growth and survival. Immunostaining showed marked up regulation of TCTP in lungs from patients with HPAH and idiopathic PAH, associated with remodeled vessels of complex lesions. Increased TCTP expression was also evident in the SU5416 rat model of severe and irreversible PAH, associated with intimal lesions, co-localizing with proliferating ECs and the adventitia of remodeled vessels, but not in the vascular media. Furthermore, silencing of TCTP expression increased apoptosis and abrogated the hyperproliferative phenotype of BOECs from HPAH patients, raising the possibility that TCTP may be a link in the emergence of apoptotic-resistant, hyperproliferative vascular cells following EC apoptosis.
Conclusions—Proteomic screening identified TCTP as a novel mediator of endothelial pro survival and growth signaling in PAH, possibly contributing to occlusive pulmonary vascular remodeling triggered by EC apoptosis.
- Received January 14, 2014.
- Revision received March 13, 2014.
- Accepted March 14, 2014.