Abstract 14426: PDGF-BB Activates Inflammatory Signaling in Pulmonary Arterial Smooth Muscle Cells from Patients with Idiopathic Pulmonary Arterial Hypertension
Background: Idiopathic pulmonary arterial hypertension (IPAH) is a refractory disease characterized by progressively increased resistance of the pulmonary arteries associated with vascular remodeling. Inappropriate increase of pulmonary artery smooth muscle cells (PASMCs) and perivascular inflammation are common in the remodeling vessels. Inhibition of platelet-derived growth factor (PDGF) signaling has recently been attracting attention as an anti-proliferative therapy for IPAH-PASMCs. However, it is unclear whether PDGF signaling is related to inflammation. We investigated whether PDGF stimulation activates inflammatory signaling including S100A8/A9 and NFkB/ cyclooxygenase-2 (COX-2) signaling in IPAH-PASMCs.
Methods and Results: PASMCs were obtained from 8 patients with IPAH undergoing lung transplantation. PDGF-BB (10 ng/mL) stimulation caused a higher growth rate of PASMCs from patients with IPAH than that of normal control PASMCs (n=6) as assessed by 3H-thymidine incorporation (normal: 179±45 vs. IPAH: 361±57% of counts before PDGF-BB, P<0.05). A time-lapse system revealed that PDGF-BB increased the migration distance of IPAH-PASMCs compared to that of normal PASMCs (P<0.0001), and imatinib (1 µg/mL), a PDGF-receptor tyrosine kinase inhibitor, inhibited PDGF-induced migration (P<0.0001). Immunofluorescence staining revealed that PDGF-BB up-regulated the expression of S100A8 in IPAH-PASMCs but not in normal PASMCs and that S100A9 is abundantly expressed in IPAH-PASMCs with or without PDGF treatment. PDGF-BB also induced translocation of NFkB from the cytoplasm to nucleus. PCR-array analysis showed that PDGF-BB up-regulated COX-2 gene expression in IPAH-PASMCs but not in normal PASMCs. PDGF-BB significantly increased mRNA level of COX-2 (P<0.05) but significantly decreased the level of prostaglandin I2 synthase in IPAH-PASMCs as assessed by quantitative PCR (P<0.05).
Conclusions: PDGF-BB up-regulates the expression of S100A8 and activates NFkB/COX2 signaling in IPAH-PASMCs. PDGF-BB activates not only proliferation but also inflammatory signaling in IPAH-PASMCs.
- © 2012 by American Heart Association, Inc.