Pigment Epithelium-Derived Factor Inhibits Neointimal Hyperplasia after Vascular Injury by Blocking NADPH Oxidase-Mediated Reactive Oxygen Species Generation

Abstract

Pigment epithelium-derived factor (PEDF) inhibits cytokine-induced endothelial cell activation through its antioxidative properties. However, the effect of PEDF on restenosis remains to be elucidated. Because the pathophysiological feature of restenosis is characterized by increased superoxide formation and accumulation of smooth muscle cells (SMCs), PEDF may inhibit this process via suppression of reactive oxygen species generation. We investigated here whether PEDF could prevent neointimal formation after balloon injury. PEDF levels were decreased in balloon-injured arteries. Adenoviral vector encoding human PEDF (Ad-PEDF) prevented neointimal formation. Expression and superoxide generation of the membrane components of NADPH oxidase, p22(phox) and gp91(phox), in the neointima were also suppressed by Ad-PEDF. Ad-PEDF reduced G(1) cyclin (cyclin D1 and E) expression and increased p27, a cyclin-dependent kinase inhibitor. In vitro, PEDF inhibited platelet-derived growth factor-BB-induced SMC proliferation and migration by blocking reactive oxygen species generation through suppression of NADPH oxidase activity via down-regulation of p22(PHOX) and gp91(PHOX). PEDF down-regulated G(1) cyclins and up-regulated p27 levels in platelet-derived growth factor-BB-exposed SMCs as well. These results demonstrate that PEDF could inhibit neointimal formation via suppression of NADPH oxidase-mediated reactive oxygen species generation. Our present study suggests that substitution of PEDF may be a novel therapeutic strategy for restenosis after balloon angioplasty.

Administration of Pigment Epithelium-Derived Factor Inhibits Left Ventricular Remodeling and Improves Cardiac Function in Rats with Acute Myocardial Infarction

“…The results were consistent with our previous observations showing that PEDF levels were decreased in damaged vascular tissues such as balloon-injured arteries, diabetic retinas, and glomeruli with Adriamycin-associated nephrotic syndrome in rats. 23,25,29 In contrast to the infarcted LV areas, we found that PEDF levels were significantly increased in cardiomyocytes of noninfarcted LV areas 4 and 8 weeks after AMI (Figure 1, B and C). Although we did not clarify here the molecular mecha- LV lesions.…”

“…14 -21 PEDF also has been shown to reduce vascular inflammation and hyperpermeability in diabetic rats, suppress thrombosis in a rat model of arterial occlusive thrombus formation, and prevent balloon injury-induced neointimal hyperplasia in rats. [22][23][24][25] These observations led us to speculate that PEDF could exert beneficial effects on LV remodeling by suppressing oxidative stress generation and inflammatory reactions in AMI. However, the protective role of PEDF against LV remodeling after AMI remains unknown.…”

Inflammation and metabolic dysfunction: links to cardiovascular diseases

“…The role of PEDF in cardiovascular diseases is not completely understood. PEDF has been shown to possess antiangiogenic effects (51) and to inhibit VEGF-induced endothelial cell migration and proliferation (56) as well as PDGF-BB-induced proliferation and migration of vascular SMCs (186). However, our group recently reported an increased proliferation of vascular SMCs upon PEDF treatment as well as the activation of inflammatory signaling pathways (64).…”

Mechanisms of PEDF-mediated protection against reactive oxygen species damage in diabetic retinopathy and neuropathy

“…It also protects against oxidative stress, which includes diabetic damage in the eye and angiogenicrelated disease , vascular injuries (Yoshida et al 2006, Nakamura et al 2007, and neurotoxicity (Araki et al 1998, Yabe et al 2005a. However, recent work has provided evidence that in uncontrolled diabetes, PEDF levels in the retina and vitreous fluids are low, which may contribute to proliferative DR (Boehm et al 2003, Yokoi et al 2007.…”