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

Masashi Kamioka1, Toshiyuki Ishibashi, Hiroshi Ohkawara

  • 1Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan.

Journal of Cellular Physiology
|October 15, 2010
PubMed

Insights

Advanced glycation end products (AGE) and the receptor for AGE (RAGE) axis contribute to diabetic vascular issues. Membrane type 1-matrix metalloproteinase (MT1-MMP) is crucial in AGE/RAGE signaling pathways, suggesting it as a therapeutic target.

Area of Science:

  • Vascular Biology
  • Molecular Medicine
  • Biochemistry

Background:

  • The advanced glycation end products (AGE)/receptor for AGE (RAGE) axis is implicated in diabetic vascular complications.
  • Membrane type 1-matrix metalloproteinase (MT1-MMP) acts as both a proteolytic enzyme and a signaling molecule.

Purpose of the Study:

  • To investigate the role of MT1-MMP in AGE/RAGE-triggered signaling pathways in smooth muscle cells (SMCs).
  • To explore the molecular interaction between RAGE and MT1-MMP in vitro and in vivo.

Main Methods:

  • Utilized cultured rabbit SMCs and diabetic rat aortae.
  • Employed small-interfering RNA (siRNA) for gene silencing.
  • Performed fluorescent immunohistochemistry and immunoprecipitation.

Main Results:

  • AGEs activated Rac1, NADPH oxidase, reactive oxygen species (ROS) generation, and NF-κB phosphorylation in SMCs.
  • MT1-MMP silencing attenuated AGE-induced signaling, including geranylgeranyl transferase I (GGTase I) activity.
  • RAGE and MT1-MMP were found to co-localize and form complexes in SMCs and vascular tissues.

Conclusions:

  • MT1-MMP plays a critical role in RAGE-activated NADPH oxidase-dependent signaling pathways.
  • MT1-MMP forms a complex with RAGE in the vasculature.
  • MT1-MMP represents a potential novel therapeutic target for diabetic vascular complications.

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