title: Secretory clusterin is upregulated in rats with pulmonary arterial hypertension induced by systemic-to-pulmonary shunts and exerts important roles in pulmonary artery smooth muscle cells.
abstract: OBJECTIVE
  Phenotype modification of pulmonary artery smooth muscle cells (PASMCs) (excessive proliferation, migration and impaired apoptosis) plays central roles in pulmonary vascular remodelling of pulmonary arterial hypertension (PAH); however, the potential mechanism and contributing factors involved in the phenotype alteration in PASMCs are still not completely elucidated. This study attempted to investigate the expression pattern of secretory clusterin (sCLU), a prosurvival protein, in systemic-to-pulmonary shunt-induced PAH rats and the potential roles of sCLU in pulmonary vascular remodelling.
  
  
  METHODS
  An original rat model of systemic-to-pulmonary shunt-induced PAH was established by combined surgery as we previously reported. Lung tissues were harvested at specific time points for real-time polymerase chain reaction, Western blot and immunohistochemisty analysis; meanwhile, plasma was collected for enzyme-linked immunosorbent assay. Cell culture experiments were performed using cultured human PASMCs (HPASMCs).
  
  
  RESULTS
  Expression of sCLU was significantly increased in lungs exposed to systemic-to-pulmonary shunt. Moreover, plasma sCLU levels were markedly elevated with the progression of PAH in rats and also presented a positive correlation with pulmonary hemodynamic indices. In vitro cell culture assay indicated that sCLU expression and secretion increased with the phenotype modification of HPASMCs; furthermore, sCLU promoted HPASMCs proliferation, migration and apoptosis resistance, at least in part, via Erk1/2 and Akt signalling pathways.
  
  
  CONCLUSIONS
  These results demonstrate that sCLU is functionally an important phenotype modulator of PASMCs, and its upregulation in lung tissues may exert a deteriorative role in pulmonary vascular remodelling.
authors: State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Fuwai Hospital, Beijing, China; Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
authors: X
authors: X
authors: Liu
authors: L
authors: L
authors: Meng
authors: J
authors: J
authors: Li
authors: J
authors: J
authors: Meng
authors: X
authors: X
authors: Teng
authors: H
authors: H
authors: Gu
authors: S
authors: S
authors: Hu
authors: Y
authors: Y
authors: Wei
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D051152:Clusterin / Q000378:metabolism*; D006973:Hypertension / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D011651:Pulmonary Artery / Q000378:metabolism* / Q000503:physiopathology; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D015533:Transcriptional Activation / Q000502:physiology; D015854:Up-Regulation
chemical_list: D051152:Clusterin
keywords: pulmonary arterial hypertension; pulmonary artery smooth muscle cells; pulmonary vascular remodelling; secretory clusterin