Green tea catechins inhibit the cultured smooth muscle cell invasion through the basement barrier Keiko Maeda, Masafumi Kuzuya , Xian Wu Cheng, Toshinobu Asai, Shigeru Kanda, Norika Tamaya-Mori, Takeshi Sasaki, Tami Shibata, Akihisa Iguchi Department of Geriatrics, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan Received 8 March 2002; received in revised form 24 June 2002; accepted 25 July 2002 Abstract Epidemiological studies suggest that green tea consumption is associated with a reduced risk of cardiovascular disease. Antioxidative properties of green tea flavonoids, catechins, have been believed to be involved in the antiatherogenic effect of green tea, since catechins inhibit low density lipoprotein oxidation. The migration of vascular smooth muscle cells (SMCs) from the tunica media to the subendothelial region is a key event in the development and progression of atherosclerosis and post-angioplasty vascular remodeling. Matrix metalloproteinases (MMPs) play a key role in these processes of SMC migration. In the present study, we investigated the effect of catechins on the gelatinolytic activity of MMP-2 that was derived from cultured bovine aortic SMCs. We also investigated the effect of catechins on the SMC invasion through the reconstituted basement membrane barrier. A major constituent of green tea catechins, ( /)-epigallocatechin gallate (EGCG), inhibited the gelatinolytic activity of MMP-2 and concanavalin A (ConA)-induced pro-MMP-2 activation without the influence of membrane-type MMP expression in SMCs. EGCG also inhibited the SMC invasion through the basement membrane barrier in a concentration-dependent manner without any influence of SMC migration across the basement membrane protein thin-coated filter. The antagonistic effects of other catechins, namely ( /)-epigallocatechin (EGC) and ( /)-epicatechin gallate (ECG), on gelatinolytic activity of MMP-2, ConA-induced pro- MMP-2 activation, or PDGF-BB-directed SMC invasion were much less pronounced than those of EGCG. Also, ( /)-catechin and ( /)-epicatechin failed to show any effect. These findings may suggest that the anti-invasive and anti-metalloproteinase activities involve at least part of the anti-atherogenic action of catechin in accordance with the antioxidant properties of catechin. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Catechin; Smooth muscle cell; Matrix metalloproteinase; Vascular remodeling; Atherosclerosis 1. Introduction It has recently been reported that green tea fla vo- noids, catechins, have various physiological activities, including anticarcinogenic [1], autimutagenic [2], anti- oxidative [3], and anti-inflammatory [4] activities. Sev- eral epidemiological studies suggest that tea consumption is associated with a reduced risk of degenerative disease such as cancer and cardiovascular disease [5  /8]. Many laboratory studies have demon- strated the inhibitory effects of tea polyphenols on tumor formation and growth. Although this inhibitory activity is believed to be mainly due to the antioxidative and possibly antiproliferative effects of polyphenolic compounds in green tea [9], the precise mechanisms are not clear. Recently, it has been demonstrated that some kinds of catechins have the ability to inhibit the activities of some matrix metalloproteinases (MMPs) [10,11], which are a family of zinc-dependent endopeptitases that are essential in the development and metastasis of cancer. This finding suggests the possible mechanism of the preventive effect of catechins on cancer develop- ment. There is increasing evidence from experimental stu- dies that free radical-mediated damage may play a role in the etiology of cardiovascular disease and that antioxidants may act in preventing this damage, possi- bly via protecting low-density lipoprotein (LDL) against  Corresponding author. Tel.:  /81-52-744-2364; fax:  /81-52-744- 2371 E-mail address: kuzuya@med.nagoya-u.ac.jp (M. Kuzuya). Atherosclerosis 166 (2003) 23  /30 www.elsevier.com/locate/atherosclerosis 0021-9150/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII:S0021-9150(02)00302-7