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.
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 approximately 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 [(3)H]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.
Nishida
M
M
Department of Internal Medicine and Molecular Science Graduate School of Medicine, Osaka University, Japan. makoton@imed2.med.osaka-u.ac.jp
Miyagawa
J
J
Yamashita
S
S
Higashiyama
S
S
Nakata
A
A
Ouchi
N
N
Tamura
R
R
Yamamori
K
K
Kihara
S
S
Taniguchi
N
N
Matsuzawa
Y
Y
D000818:Animals; D015703:Antigens, CD / Q000032:analysis* / Q000494:pharmacology; D001011:Aorta / Q000737:chemistry; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000737:chemistry; D004815:Epidermal Growth Factor / Q000032:analysis / Q000378:metabolism*; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D060245:Tetraspanin 29
D015703:Antigens, CD; C554869:CD9 protein, human; C554870:Cd9 protein, mouse; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D060245:Tetraspanin 29; D004815:Epidermal Growth Factor