Abstract
Background: Pulmonary arterial hypertension (PAH) is associated with suppressed apoptosis of pulmonary artery smooth muscle cells (PASMCs). Survivin has been reported to suppress caspase activities and plays an important role in the mechanism of suppressed apoptosis. In this study, we investigated whether epoprostenol exerts the pro-apoptotic effects by inhibiting the expression of survivin in PASMCs. Methods: We studied the induction of apoptosis by epoprostenol in PAH-PASMCs (n = 5) and non-PAH-PASMCs (n = 3). We investigated the expression of survivin in lung tissues obtain from 5 idiopathic PAH patients and 3 non-PAH patients, and in PAH-PASMCs and non-PAH-PASMCs by immunocytochemical analysis. We examined the protein level of survivin in PAH-PASMCs treated with epoprostenol or diluents by western blotting. We also examined the time course of mRNA level of survivin treated with epoprostenol or diluents by quantitative RT-PCR. Results: TUNEL-positive cells, caspase-3- and -7-active cells, condensation of chromatin along the nuclear membrane, and fragmentation of the nucleus were found in PAH-PASMCs treated with epoprostenol. Epoprostenol significantly induced apoptosis in PAH-PASMCs compared with that in non-PAH-PASMCs (5.64 ± 0.82% versus 0.64 ± 0.25%; P < 0.05). Survivin was expressed in lung tissues obtained from idiopathic PAH patients but not from non-PAH patients. Survivin was also expressed in PAH-PASMCs but not non-PAH-PASMCs with immunocytochemical analysis. Treatment with epoprostenol for 24 hours significantly suppressed the protein level of survivin by 52% compared with treatment with diluents in PAH-PASMCs (P < 0.05). Epoprostenol significantly decreased the mRNA level of survivin after 12 hours (29%; P < 0.05) and 24 hours (10%; P < 0.05) treatment compared with diluents. Conclusions: Epoprostenol can induce the apoptosis by inhibiting the expression of survivin in PAH-PASMCs.
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