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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1236.)
© 2000 American Heart Association, Inc.

Vascular Biology

Localization of CD9, an Enhancer Protein for Proheparin-Binding Epidermal Growth Factor–Like Growth Factor, in Human Atherosclerotic Plaques

Possible Involvement of Juxtacrine Growth Mechanism on Smooth Muscle Cell Proliferation

Makoto Nishida; Jun-ichiro Miyagawa; Shizuya Yamashita; Shigeki Higashiyama; Atsuyuki Nakata; Noriyuki Ouchi; Ritsu Tamura; Katsumi Yamamori; Shinji Kihara; Naoyuki Taniguchi; Yuji Matsuzawa

From the Department of Internal Medicine and Molecular Science Graduate School of Medicine (M.N., J.M., S.Y., A.N., N.O., R.T., K.Y., S.K., Y.M.), Osaka University, and the Department of Biological Chemistry and Molecular Pharmacology (S.H., N.T.), Osaka University Medical School, Osaka, Japan.

Correspondence to Makoto Nishida, MD, Department of Internal Medicine and Molecular Science Graduate School of Medicine, B5 Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail makoton{at}imed2.med.osaka-u.ac.jp

Abstract—Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), a member of the EGF family, has a potent mitogenic activity for vascular smooth muscle cells (SMCs). We previously reported that HB-EGF is involved in atherogenesis of human aorta and coronary arteries. ProHB-EGF (the membrane-anchored form of HB-EGF) has also been demonstrated to possess a mitogenic activity, which is 30-fold increased when coexpressed with CD9 in mouse L cells. Thus, in the process of atherogenesis, CD9 may be involved in the proliferation of SMCs. We immunohistochemically investigated the localization of CD9 and proHB-EGF in the human aorta and coronary arteries. In normal aorta and coronary arteries, CD9 immunostaining was virtually negative, whereas proHB-EGF immunostaining was positive, especially in the arteries of babies. In contrast, in atherosclerotic lesions, some intimal SMCs were strongly positive for CD9 and proHB-EGF immunostaining. The juxtacrine growth activities of human aortic SMCs were inhibited in vitro by adding neutralization antibodies for CD9 or adding the specific inhibitor of HB-EGF. Besides, coexpressed CD9 and proHB-EGF cells markedly incorporated [³H]thymidine into the SMCs. CD9 is localized immunohistochemically in the SMCs of the atherosclerotic aorta and coronary arteries. CD9, when coexpressed with proHB-EGF, enhances proHB-EGF activities for SMC growth in a so-called juxtacrine manner in vitro and may be involved in atherogenesis.

Key Words: vascular smooth muscle cells • CD9 • heparin-binding epidermal growth factor–like growth factor • atherosclerosis

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