Abstract 280: Pigment Epithelium-Derived Factor (PEDF) Inhibits Neointima Formation by Suppressing NADPH Oxidase-Mediated Reactive Oxygen Species Generation
We have previously found that pigment epithelium-derived factor (PEDF), a glycoprotein with neuronal differentiating activity, inhibited tumor necrosis factor-a- or angiotensin II-induced endothelial cell activation through its anti-oxidative properties, thus suggesting that PEDF may play a protective role against endothelial injury. However, the effects of PEDF on restenosis, a frequent complication of coronary angioplasty, remain to be elucidated. The pathophysiological feature of restenosis is characterized by increased superoxide formation and accumulation of smooth muscle cells (SMCs) within the intimal area via overexpression of platelet-derived growth factor (PDGF), it is conceivable that PEDF inhibits this process via suppression of reactive oxygen species (ROS) generation. Accordingly, we investigated here whether and how an overexpression of PEDF could prevent neointima formation in balloon-injured rat carotid arteries. Fourteen days after balloon injury, intima/media (I/M) ratio was increased by about 40-folds of that of non-injured artery. Adenoviral vector encoding human PEDF (Ad-PEDF) decreased the I/M ratio by 80%. Expression levels of two membrane components of NADPH oxidase, p22phox and gp91phox and superoxide generation in the neointima were also significantly blocked by Ad-PEDF. Further, Ad-PEDF not only reduced expression levels of G1 cyclins, cyclin D and E, but also stimulated p27, a cyclin-dependent kinase inhibitor that causes G1 arrest, thus decreasing the number of proliferating cell nuclear antigen-positive SMCs in the neointima. In vitro, 10 nM PEDF was found to inhibit PDGF-B-induced SMC proliferation and migration by blocking ROS generation via suppression of NADPH oxidase activity. PEDF down-regulated cyclin D and up-regulated p27 levels in PDGF-BB-exposed SMC as well. These results demonstrate that PEDF could prevent the neointima formation by suppressing the proliferation and migration of SMCs via inhibition of NADPH oxidase-mediated ROS generation. Our present study suggests that PEDF may be a novel therapeutic target for the treatment of restenosis after balloon angioplasty.