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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:1680-1687.)
© 1995 American Heart Association, Inc.

Articles

Increased Mitogenic Response to Heparin-Binding Epidermal Growth Factor–like Growth Factor in Vascular Smooth Muscle Cells of Diabetic Rats

Kazuto Fukuda; Yoshiaki Inui; Sumio Kawata; Shigeki Higashiyama; Yukihiko Matsuda; Yuichi Maeda; Takumi Igura; Shingo Yoshida; Naoyuki Taniguchi; Yuji Matsuzawa

From the Second Department of Internal Medicine and Department of Biochemistry (S.H., N.T.), Osaka University Medical School, Osaka, Japan.

Correspondence to Kazuto Fukuda, MD, Second Department of Internal Medicine, or Shigeki Higashiyama, MD, Department of Biochemistry, Osaka University Medical School, 2-2 Yamadaoka, Suita 565, Japan.

Abstract We investigated the mitogenic effects of heparin-binding epidermal growth factor–like growth factor (HB-EGF) in vascular smooth muscle cells (SMCs) obtained from rats with streptozotocin (STZ)-induced diabetes and evaluated the role of heparan sulfate proteoglycan (HSPG) in inducing these effects. HB-EGF significantly increased DNA synthesis in the SMCs of diabetic rats (STZ-SMCs) compared with control rats (control SMCs). However, the mitogenic effects of EGF, which shares EGF receptors with HB-EGF, and basic fibroblast growth factor, another heparin-binding growth factor, were similar in STZ-SMCs and control SMCs. The mitogenic response to HB-EGF in SMCs of insulin-treated diabetic rats was similar to the response in control SMCs. HB-EGF–induced autophosphorylation of EGF receptors was increased in STZ-SMCs compared with control SMCs, although the number of EGF receptors in STZ-SMCs was 40% of that in controls. This increased mitogenic response to HB-EGF in STZ-SMCs was completely inhibited by treatment with heparitinase, chlorate, and a synthetic peptide corresponding to the heparin-binding domain of HB-EGF. Compared with heparan sulfate isolated from control SMCs, heparan sulfate isolated from STZ-SMCs was of smaller molecular size and caused a greater mitogenic effect of HB-EGF. These findings suggest that the mitogenic response to HB-EGF is increased in SMCs of diabetic rats. Changes in cell-associated heparan sulfate in STZ-SMCs may be related to the increased mitogenic response to HB-EGF.

Key Words: HB-EGF • vascular smooth muscle cells • heparan sulfate proteoglycan • diabetes mellitus

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