4.7 Article

Involvement of Membrane Type 1-Matrix Metalloproteinase (MT1-MMP) in RAGE Activation Signaling Pathways

期刊

JOURNAL OF CELLULAR PHYSIOLOGY
卷 226, 期 6, 页码 1554-1563

出版社

WILEY-BLACKWELL
DOI: 10.1002/jcp.22492

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资金

  1. Japan Society for the Promotion of Science [19590804, 20790538, 21590935]
  2. Takeda Science Foundation
  3. Uehara Memorial Foundation
  4. Fukuda Foundation for Medical Technology
  5. Fukushima Medical University
  6. Grants-in-Aid for Scientific Research [21590340, 21590935, 23659170, 21390057, 20790538] Funding Source: KAKEN

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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-kappa B 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. (C) 2010 Wiley-Liss, Inc.

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