Cardiovascular Research Advance Access [Accepted Manuscript] published online on March 13, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn071
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High levels and inflammatory effects of soluble CXCL16 in coronary artery disease - down-regulatory effects of statins
1 Research Institute for Internal Medicine, Rikshospitalet-Radiumhospitalet Medical Center, University of Oslo, Norway
2 Section of Clinical Immunology and Infectious Diseases, and Rikshospitalet-Radiumhospitalet Medical Center, University of Oslo, Norway
3 Department of Cardiology, Rikshospitalet-Radiumhospitalet Medical Center, University of Oslo, Norway
Address for correspondence: Pål Aukrust, MD, PhD Section of Clinical Immunology and Infectious Diseases Rikshospitalet-Radiumhospitalet Medical Center, N-0027 Oslo, Norway Phone: 47-23070000, Fax: 47-23073630, e-mail: pal.aukrust{at}rikshospitalet.no
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: 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, 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.
Results: Our main findings were: 1) Patients with stable (n=40) and unstable (n=40) angina had elevated plasma levels of CXCL16 compared to controls (n=20). 2) 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. 3) In vitro, atorvastatin significantly decreased the interleukin (IL)-1β-mediated release of CXCL16 from PBMC and endothelial cells. 4) The 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 ADAM10. 5) Soluble CXCL16 increased the release of IL-8, monocyte chemoattractant peptide 1, and matrix metalloproteinases in vascular smooth muscle cells 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.
Time for primary review: 16 days
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