Pigment epithelium-derived factor (PEDF) prevents platelet activation and aggregation in diabetic rats by blocking deleterious effects of advanced glycation end products (AGEs)

Background: Alteration of platelet function contributes to microthrombus formation and may play an important role in the pathogenesis of diabetic vascular complications. In addition, there is a growing body of evidence that oxidative stress generation is involved in platelet activation and aggregation in vivo. Since we have recently found that pigment epithelium-derived factor (PEDF) inhibits thrombus formation in rats through its anti-oxidative properties, we investigated here whether PEDF prevented platelet activation and aggregation in diabetic or advanced glycation end products (AGEs)-injected rats. Methods and Results: Experimental diabetes was induced by injecting streptozotocin to Sprague-Dawley rats. Diabetic or non-diabetic Sprague-Dawley rats were injected intravenously with or without 1 mg AGEs-bovine serum albumin or non-glycated bovine serum albumin in the presence or absence of 10 μg PEDF everyday. Administration of PEDF or pyridoxal phosphate, an inhibitor of AGEs formation, inhibited platelet P-selectin expression and aggregation by suppressing NADPH oxidase-driven superoxide generation, and subsequently ameliorated a shortened tail vein bleeding time in diabetic rats. Further, intravenous administration of AGEs to normal rats mimicked the effects of diabetes on platelet activation and bleeding time, which were also blocked by simultaneous administration of PEDF. Conclusions: These results demonstrated for the first time that PEDF inhibited platelet activation and aggregation in diabetic rats through its anti-oxidative properties. Our present study suggests that PEDF may play a protective role against diabetic vascular complications by attenuating the deleterious effects of AGEs on platelets.