Role of hepatocyte growth factor in endothelial regulation: prevention of high D-glucose-induced endothelial cell death by prostaglandins and phosphodiesterase type 3 inhibitor

Summary Injury of endothelial cells (EC) has been postulated as the initial trigger of the progression of atherosclerosis in patients with diabetes mellitus. We previously reported that decrease in a novel endothelium-specific growth factor, hepatocyte growth factor (HGF), by high d-glucose might be a trigger of endothelial injury. However, the physiological role of the local vascular HGF system has not yet been clarified. To investigate the role of HGF in endothelial injury, we initially examined the effects of HGF on endothelial injury induced by serum deprivation. Decrease in EC number by serum deprivation was significantly attenuated by addition of HGF as well as recombinant basic fibroblast growth factor, whereas vascular endothelial growth factor showed no effect. Apoptotic changes in EC induced by serum deprivation were also significantly attenuated by addition of HGF (p < 0.01). Given the protective action of HGF, we next studied the physiological role of local HGF production in endothelial regulation. We focused on the protective actions of prostaglandin (PG) I₂, PGE and a phosphodiesterase type 3 inhibitor (cilostazol) on endothelial injury by high glucose, since these agents are widely used in the treatment of peripheral arterial disease which is frequently observed in diabetic patients. Treatment of human aortic EC with PGE₁, PGE₂, and a PGI₂ analogue (beraprost sodium) as well as cilostazol stimulated EC growth. HGF concentration in conditioned medium from EC treated with PGE₁, PGE₂ or PGI₂ analogue as well as cilostazol was significantly higher than that with vehicle (p < 0.01). Interestingly, treatment with PGI₂ analogue or cilostazol attenuated high d-glucose-induced EC death, which was abolished by neutralizing anti-HGF antibody. Moreover, decreased local HGF production by high d-glucose was also significantly attenuated by PGI₂ analogue or cilostazol. Finally, we tested the effects of PGE, PGI₂ analogue and cilostazol on local HGF production in human aortic vascular smooth muscle cells (VSMC). Although high d-glucose treatment resulted in a significant increase in VSMC number, PGI₂ analogue and/or cilostazol treatment had no effects on VSMC growth. However, the decrease in local HGF production by high d-glucose was significantly attenuated by addition of PGI₂ analogue or cilostazol. Overall, this study demonstrated that treatment with PGE, PGI₂ analogue or cilostazol prevented aortic EC death induced by high d-glucose, probably through the activation of local HGF production. Increased local vascular HGF production by prostaglandins and cilostazol may prevent endothelial injury, potentially resulting in the improvement of peripheral arterial disease. [Diabetologia (1997) 40: 1053–1061] Received: 17 February 1997 and in revised form: 7 May 1997