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ATP stimulates MMP-2 release from human aortic smooth muscle cells via JNK signaling pathway

William P Robinson1, Christelle D Douillet, Peter M Milano

  • 1Department of Surgery, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7228, USA.

American Journal of Physiology. Heart and Circulatory Physiology
|December 20, 2005
PubMed

Insights

Extracellular nucleotides, like ATP, stimulate the release of matrix metalloproteinase-2 (MMP-2) from human aortic smooth muscle cells (HASMCs). This finding suggests a new link between vascular stress, inflammation, and aortic aneurysm development.

Area of Science:

  • Vascular Biology
  • Cell Signaling
  • Biochemistry

Background:

  • Matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-2 (TIMP-2) release from aortic smooth muscle cells is linked to aortic aneurysm pathogenesis.
  • The role of extracellular nucleotides in modulating MMP and TIMP release from these cells is largely unknown.
  • Extracellular nucleotides are known regulators of vascular smooth muscle cell metabolism under stress.

Purpose of the Study:

  • To investigate whether extracellular nucleotides modulate MMP-2 and TIMP-2 release from human aortic smooth muscle cells (HASMCs).
  • To identify the specific purinergic receptors and signaling pathways involved in nucleotide-mediated MMP-2 and TIMP-2 release.

Main Methods:

  • Human aortic smooth muscle cells (HASMCs) were treated with various nucleotides (ATP, adenosine, UTP) with and without interleukin-1beta (IL-1beta).
  • Apyrase (ATP-degrading enzyme) and specific MAPK pathway inhibitors (ERK1/2, JNK, p38) were used to elucidate signaling mechanisms.
  • MMP-2 and TIMP-2 levels in cell supernatants were quantified using ELISA and Western blotting.

Main Results:

  • ATP, adenosine, and UTP significantly stimulated MMP-2 release from HASMCs, particularly in the presence of IL-1beta.
  • ATP alone also increased MMP-2 release, and this effect was significantly reduced by apyrase.
  • The rank order of agonist potency suggested activation of P2Y receptors, and ATP-induced MMP-2 release was dependent on the JNK signaling pathway.

Conclusions:

  • Extracellular nucleotides are novel stimulants of MMP-2 release from HASMCs.
  • Nucleotide signaling, particularly via the JNK pathway, may represent a critical mechanism linking vascular stress and inflammation to aortic aneurysm development.

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