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High levels and inflammatory effects of soluble CXC ligand 16 (CXCL16) in coronary artery disease: down-regulatory effects of statins

  1. Camilla Smith1,
  2. Bente Halvorsen1,
  3. Kari Otterdal1,
  4. Torgun Wæhre1,
  5. Arne Yndestad1,
  6. Børre Fevang1,
  7. Wiggo J. Sandberg1,
  8. Unni M. Breland1,
  9. Stig S. Frøland1,2,
  10. Erik Øie3,
  11. Lars Gullestad3,
  12. Jan K. Damås1,2 and
  13. Pål Aukrust1,2,*
  1. 1Research Institute for Internal Medicine, Rikshospitalet Medical Center, University of Oslo, Oslo, Norway
  2. 2Section of Clinical Immunology and Infectious Diseases, Rikshospitalet Medical Center, University of Oslo, Sognsvannsveien 20, N-0027 Oslo, Norway
  3. 3Department of Cardiology, Rikshospitalet Medical Center, University of Oslo, Oslo, Norway
  1. *Corresponding author. Tel: +47 23070000; fax: +47 23073630. E-mail address: pal.aukrust{at}rikshospitalet.no
  • Received September 17, 2007.
  • Revision received March 7, 2008.
  • Accepted March 10, 2008.

Abstract

Aims CXC ligand 16 (CXCL16) may be involved in inflammation and lipid metabolism, and we hypothesized a role for this chemokine in coronary artery disease (CAD).

Methods and results We performed clinical studies in CAD patients as well as experimental studies in cells with relevance to atherogenesis [i.e. endothelial cells, vascular smooth muscle cells (SMC), and peripheral blood mononuclear cells (PBMC)]. We also examined the ability of HMG-CoA reductase inhibitors (statins) to modulate CXCL16 levels both in vivo and in vitro. Our main findings were: (i) patients with stable (n = 40) and unstable (n = 40) angina had elevated plasma levels of CXCL16 compared with controls (n = 20); (ii) low-dose simvastatin (20 mg qd, n = 15) and high-dose atorvastatin (80 mg qd, n = 9) down-regulated plasma levels of CXCL16 during 6 months of therapy; (iii) in vitro, atorvastatin significantly decreased the interleukin (IL)-1β-mediated release of CXCL16 from PBMC and endothelial cells; (iv) attenuating effect of atorvastatin on the IL-1β-mediated release of CXCL16 in PBMC seems to involve post-transcriptional modulation as well as down-regulation of CXCL16 release through inhibition of the protease a disintegrin and metalloproteinase 10 (ADAM10); (v) soluble CXCL16 increased the release of IL-8, monocyte chemoattractant peptide 1, and matrix metalloproteinases in vascular SMC and increased the release of IL-8 and monocyte chemoattractant peptide 1 in PBMC, with particularly enhancing effects in cells from CAD patients.

Conclusion Our findings suggest that soluble CXCL16 could be linked to atherogenesis not only as a marker of inflammation, but also as a potential inflammatory mediator.

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    1. Cardiovasc Res (2008) 79 (1): 195-203. doi: 10.1093/cvr/cvn071 First published online: March 13, 2008
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