Impaired endothelial dysfunction in diabetes mellitus rats was restored by oral administration of prostaglandin I2 analogue

Abstract

We have previously reported that a decrease in hepatocyte growth factor (HGF), which has many protective functions against endothelial damage by high D-glucose, might be a trigger of endothelial injury. However, the regulation of vascular HGF in diabetes mellitus (DM) has not been clarified in vivo, although vascular disease is frequently observed in DM patients. In addition, our previous report revealed that a prostaglandin I2 (PGI2) analogue prevented endothelial cell death through the induction of vascular HGF production in cultured human epithelial cells. Thus, in this study, we examined the effects of a PGI2 analogue in the regulation of the local HGF system using DM rats. A PGI2 analogue (beraprost sodium; 300 and 600 μg/kg per day) or vehicle was administered to 16-week-old DM rats induced by administration of streptozotocin for 28 days. Endothelial function was evaluated by the vasodilator response to acetylcholine, and the expression of vascular HGF mRNA was measured by Northern blotting. Of importance, expression of HGF mRNA was significantly decreased in the blood vessels of DM rats as compared with non-DM (P<0.01). In addition, the in vitro vasodilator response of the abdominal aorta to acetylcholine was markedly impaired in DM rats. Importantly, the vasodilator response was restored by PGI2 treatment in a dose-dependent manner (P<0.01), whereas N(omega)-nitro-L-arginine methyl ester inhibited the restoration of endothelial function. Of particular interest, vascular HGF mRNA and protein were significantly increased in the blood vessels of DM rats treated with PGI2 as compared with vehicle. Similarly, an increase in HGF protein was also confirmed by immunohistochemical analysis. In addition, the specific HGF receptor, c-met, was also increased by PGI2 treatment. Overall, this study demonstrated that treatment with a PGI2 analogue restored endothelial dysfunction in DM rats, accompanied by the induction of vascular HGF and c-met expression. Increased local vascular HGF production by a PGI2 analogue may prevent endothelial injury, potentially resulting in the improvement of endothelial dysfunction.