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

Aim: 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.

Conclusion: 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.