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Hepatocyte Growth Factor Prevents Endothelial Cell Death Through Inhibition of bax Translocation From Cytosol to Mitochondrial Membrane

¹ Department of Geriatric Medicine, Graduate School of Medicine, Osaka University, Suita, Japan
² Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Suita, Japan
³ Division of Biochemistry, Department of Oncology, Biomedical Research Center, Graduate School of Medicine, Osaka University, Suita, Japan

Injury of endothelial cells has been postulated to be an initial trigger of the progression of atherosclerosis in patients with diabetes. Previously, we demonstrated high D-glucose induced endothelial apoptosis through the bax-caspase pathway and the potential contribution of hepatocyte growth factor (HGF) to the pathogenesis of endothelial dysfunction. In this study, we analyzed the molecular mechanisms of the protective actions of HGF against endothelial cell death under high D-glucose conditions. High concentrations of D-glucose resulted in a significant increase in apoptosis and necrosis. In contrast, HGF attenuated high D-glucose-induced apoptosis and necrosis (P < 0.01). High D-glucose significantly increased bax protein, but not bcl-2, and activated caspase 3-like and 9, whereas HGF significantly increased bcl-2 expression without affecting bax level and attenuated the increase in caspase 3 and 9 activity. Interestingly, high D-glucose resulted in translocation of bax protein from cytosol to the mitochondrial membrane, whereas HGF inhibited the bax translocation. Importantly, this bax translocation was also completely blocked by overexpressed bcl-2. These findings suggest that HGF can activate bcl-2 expression and inhibit translocation of bax protein upstream of the mitochondria, thereby leading to the inhibition of caspase 3 and 9 activation. HGF may be an important factor in the maintenance of endothelial function.

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