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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:1962-1968.)
© 1997 American Heart Association, Inc.

Articles

High Concentration of Glucose Increases Mitogenic Responsiveness to Heparin-Binding Epidermal Growth Factor–like Growth Factor in Rat Vascular Smooth Muscle Cells

Kazuto Fukuda; Sumio Kawata; Yoshiaki Inui; Shigeki Higashiyama; Yukihiko Matsuda; Takumi Igura; Shinji Tamura; Naoyuki Taniguchi; ; Yuji Matsuzawa

From the Second Department of Internal Medicine (K.F., S.K., Y.I., Y. Matsuda, T.I., S.T., Y. Matsuzawa) and the Department of Biochemistry (S.H., N.T.), Osaka University Medical School, Japan.

Correspondence to Kazuto Fukuda, MD, Second Department of Internal Medicine, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565, Japan. E-mail ikura{at}imed2.med.osaka-u.ac.jp

Abstract The effect of a high extracellular glucose concentration on the mitogenic response of rat vascular smooth muscle cells (SMCs) to heparin-binding epidermal growth factor–like growth factor (HB-EGF) was investigated. The mitogenic effect of HB-EGF was significantly greater in SMCs cultured in high glucose (25 mmol/L) than in cells cultured in low glucose (5.5 mmol/L) or at high osmolarity (5.5 mmol/L glucose plus 19.5 mmol/L mannitol). The mitogenic effect of epidermal growth factor (EGF), which shares the EGF receptor with HB-EGF, was not affected by glucose concentration. The mitogenic effect of HB-EGF was greater when incubated with heparan sulfate (HS) isolated from SMCs cultured in high glucose than with HS from cells cultured in low glucose. HS synthesized by cells in high glucose was of smaller molecular size and less sulfated than HS synthesized by cells in low glucose. The abundance of mRNA encoding HS-N-deacetylase/N-sulfotransferase (HS-NdAc/NST), a regulatory enzyme in the biosynthesis of HS, was decreased by high glucose in a protein kinase C–independent manner. These observations suggest that the enhanced mitogenic response to HB-EGF in SMCs cultured in high glucose may be attributable to changes in cell-associated HS. Downregulation of HS-NdAc/NST gene expression by high glucose may be related to the altered HS biosynthesis.

Key Words: HB-EGF • vascular smooth muscle cells • heparan sulfate • glucose • heparan sulfate N-deacetylase/N-sulfotransferase

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