Involvement of membrane type 1-matrix metalloproteinase (MT1-MMP) in RAGE activation signaling pathways

✍ Scribed by Masashi Kamioka; Toshiyuki Ishibashi; Hiroshi Ohkawara; Ryoji Nagai; Koichi Sugimoto; Hironori Uekita; Takanori Matsui; Sho-Ichi Yamagishi; Katsuya Ando; Takayuki Sakamoto; Nobuo Sakamoto; Yoh Takuwa; Ikuo Wada; Masashi Shiomi; Yukio Maruyama; Yasuchika Takeishi

• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: English
• Weight: 807 KB
• Volume: 226
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/jcp.22492

✦ Synopsis

Abstract

An advanced glycation end products (AGE)/a receptor for AGE (RAGE) axis plays a key role in diabetic vascular complications. Membrane type 1‐matrix metalloproteinase (MT1‐MMP) has been shown to function not only as a proteolytic enzyme but also as a signaling molecule. In this study, we investigated the role of MT1‐MMP in the AGE/RAGE‐triggered signaling pathways in cultured rabbit smooth muscle cells (SMCs) and the molecular interaction between RAGE and MT1‐MMP in vitro and in vivo. In SMCs, AGE‐activated Rac1 and p47^phox^ within 1 min, NADPH oxidase activity and reactive oxygen species (ROS) generation within 5 min, and NF‐κB phosphorylation within 15 min, thereby inducing redox‐sensitive molecular expression. Silencing of RAGE by small‐interfering RNA (siRNA) blocked the AGE‐induced signaling pathways. AGE‐induced geranylgeranyl transferase I (GGTase I) activity, Rac1·p47^phox^ activation, NADPH oxidase activity, ROS generation, and molecular expression were also markedly attenuated by silencing of MT1‐MMP. An inhibitor of GGTase I mimicked the effects of MT1‐MMP‐specific siRNA. Fluorescent immunohistochemistry revealed that MT1‐MMP was partially co‐localized with RAGE in SMCs, and RAGE was found to form a complex with MT1‐MMP in both cultured SMCs and the aortae of diabetic rats by immunoprecipitation. Furthermore, MT1‐MMP and RAGE formed a complex in the aortic atherosclerotic lesions of hyperlipidemic rabbits. We show that MT1‐MMP plays a crucial role in RAGE‐activated NADPH oxidase‐dependent signaling pathways and forms a complex with RAGE in the vasculature, thus suggesting that MT1‐MMP may be a novel therapeutic target for diabetic vascular complications. J. Cell. Physiol. 226: 1554–1563, 2011. © 2010 Wiley‐Liss, Inc.