High Glucose and Hyperosmolarity Increase Heparin‐Binding Epidermal Growth Factor‐like Growth Factor (HB‐EGF) Production in Cultured Human Aortic Endothelial Cells

Abstract

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) has been shown to be a potent smooth muscle cell (SMC) mitogen and chemoattractant, and might be a candidate factor for the progression of atherosclerosis. We have investigated the effects of high glucose and hyperosmolarity on HB-EGF production in cultured human aortic endothelial cells. Following the culture of the cells for 2 days with high concentrations of glucose or in the hyperosmolar conditions, we measured the content of HB-EGF and the rate of production in the cells using a semi-quantitative immunofluorescent technique and a metabolic radiolabelling method. With high glucose (16.6 mmol) and hyperosmolar conditions (glucose 5.5 mmol + mannitol 11.1 mmol or glucose 5.5 mmol + raffinose 11.1 mmol), the content of HB-EGF was significantly increased and the metabolic rate was also significantly increased (more than a twofold increase, compared to that of 5.5 mmol glucose). In conclusion, conditions of high glucose or hyperosmolarity increase HB-EGF production in human aortic endothelial cells. These results suggest that diabetic macroangiopathy might be attributed at least in part to HB-EGF-related vascular changes which may be induced by glucose.

Osmotic Induction of Angiogenic Growth Factor Expression in Human Retinal Pigment Epithelial Cells

“…It has been shown previously that hypoxia induces the secretion of VEGF, but not of bFGF, from RPE cells [ 38 ]. The present data are also in agreement with previous studies using different cell systems which showed that extracellular hyperosmolarity induces the expression of HB-EGF [ 52 , 53 ]. The increase in the level of VEGF mRNA and the delayed decrease in the level of PEDF mRNA induced by chemical hypoxia ( Fig 1E ) are consistent with previous studies which showed that hypoxia induces upregulation of VEGF and downregulation of PEDF in the retina [ 4 , 54 ].…”

Hypertonic induction of COX-2 expression in renal medullary epithelial cells requires transactivation of the EGFR

“…A related phenomenon was observed recently in normal human renal tissue (32). Moreover, expression of HB-EGF appears to be itself osmotically regulated (1,27). Interestingly, HB-EGF and CD9 also interact with A disintegrin and metalloprotease domain 10 (also known as Kuzbanian), and this metalloproteinase may mediate the ectodomain shedding and autocrine action of EGFR ligands such as HB-EGF (46).…”

An oxidative stress mechanism mediates chelerythrine‐induced heparin‐binding EGF‐like growth factor ectodomain shedding

“…Our present observations further implicate stress‐initiated mechanisms in HB‐EGF processing. Stress signals have been demonstrated to upregulate HB‐EGF at the mRNA and protein levels in vitro and in vivo [Miyagawa et al, 1995; Asakawa et al, 1996; Igura et al, 1996; Park et al, 1999; Nguyen et al, 2000]. Our findings and those of others suggest that HB‐EGF cleavage‐secretion is also likely to be upregulated in many of these conditions and that this process may play a physiologic role in the maintenance of tissue homeostasis.…”