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Involvement of membrane type 1‐matrix metalloproteinase (MT1‐MMP) in RAGE activation signaling pathways
Author(s) -
Kamioka Masashi,
Ishibashi Toshiyuki,
Ohkawara Hiroshi,
Nagai Ryoji,
Sugimoto Koichi,
Uekita Hironori,
Matsui Takanori,
Yamagishi ShoIchi,
Ando Katsuya,
Sakamoto Takayuki,
Sakamoto Nobuo,
Takuwa Yoh,
Wada Ikuo,
Shiomi Masashi,
Maruyama Yukio,
Takeishi Yasuchika
Publication year - 2011
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.22492
Subject(s) - rage (emotion) , nadph oxidase , signal transduction , microbiology and biotechnology , glycation , matrix metalloproteinase , reactive oxygen species , rac1 , chemistry , cell signaling , gene silencing , biology , receptor , biochemistry , neuroscience , gene
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.