Abstract 16546: Prostaglandin I2 Induced Pulmonary Artery Smooth Muscle Cells Apoptosis via Upregulation of Fas Ligand in Idiopathic Pulmonary Arterial Hypertension
Introduction: Pulmonary arterial remodeling with pulmonary arterial hypertension (PAH) is associated with impaired apoptosis of pulmonary artery smooth muscle cells (PASMCs). Although prostaglandin I2 (PGI2) is expected to have reversal remodeling effect, it has not been clarified whether PGI2 has pro-apoptotic effects.
Hypothesis: We assessed the hypothesis that PGI2 induced PASMCs apoptosis via upreguration of Fas ligand, an apoptosis-inducing member of the TNF cytokine family.
Methods: We obtained PASMCs from 5 idiopathic PAH patients and 3 non-PAH patients. We investigated pro-apoptotic effects of PGI2 in PAH-PASMCs and non-PAH-PASMCs by TUNEL assays, caspase-3,-7 assays and transmission electron microscopy. We examined the mRNA and protein level of Fas ligand in PAH-PASMCs treated with PGI2 or diluents by qRT-PCR and western blotting. We also examined cAMP level in PAH-PASMCs treated with PGI2 or diluents by ELISA.
Results: TUNEL-positive, caspase-3, 7-active cells and fragmentation of the nucleus were detected in PAH-PASMCs treated with PGI2. The percentage of apoptotic cells induced by PGI2 in PAH-PASMCs was significantly higher than that in non-PAH-PASMCs (4.59±1.76 versus 0.72±0.32% P<0.05). PGI2 significantly increased the mRNA level of Fas ligand by 4.12 fold compared with diluents. PGI2 significantly increased the protein level of Fas ligand by 1.65 fold compared with diluents in PAH-PASMCs (P<0.05). PGI2 significantly increase cAMP levels compared with diluents in a concentration-dependent manner in PAH-PASMCs (0.1 ng/ml, 1.0 ng/ml, 10 ng/ml; treated/control = 1.09±0.18, 2.07±0.82, 3.86±1.61, respectively). IP receptor antagonist inhibited the elevation of cAMP levels by PGI2 (1.0ng/ml) (PGI2 versus. IP receptor antagonist+PGI2; treated/control = 1.54±0.21 vs. 0.55±0.23; P<0.05). IP receptor antagonist suppressed the PASMCs apoptosis induced by PGI2 (1.0ng/ml) (PGI2 versus. IP receptor antagonist+PGI2; treated/control = 4.59±1.76% versus 0.65±0.54% P<0.05).
Conclusions: PGI2 induces the PASMCs apoptosis by Fas ligand upregulation in idiopathic PAH.
- © 2010 by American Heart Association, Inc.