© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Statins (HMG-CoA reductase inhibitors) reduce CD40 expression in human vascular cells
aCardiology Division, Department of Medicine, University Hospital, Geneva Medical School, Foundation for Medical Research, 64 Avenue Roseraie, 1211 Geneva 4, Switzerland
bSerono Pharmaceutical Research Institute, Geneva, Switzerland
cDivision of Cardiology, Cardiovascular Research, Institute of Physiology and Division of Cardiology, Cardiovascular Center, University Hospital, Zurich, Switzerland
brenda.kwakchanson{at}medecine.unige.ch
* Corresponding author. Tel.: +41-22-382-7233; fax: +41-22-382-7245.
Objective: HMG-CoA reductase inhibitors (statins) possess anti-inflammatory and immunomodulatory properties that are independent of their lipid-lowering action. As the CD40–CD40L signaling pathway is implicated in the modulation of inflammatory responses between vascular cells, involving adhesion molecules, pro-inflammatory cytokines, chemokines, we sought to investigate the potential role of statins in regulating the expression of CD40. Methods and Results: Using Western blot, flow cytometry and immunohistochemistry analyses, we observed that four different statins reduced IFN-
-induced CD40 expression in human vascular cells (endothelial cells, smooth muscle cells, macrophages and fibroblasts). This effect was dose-dependent (from 5 µM to 80 nM) and reversed by addition of L-mevalonate. Activation of vascular cells by human recombinant CD40L, as measured by ELISA for IL-6, IL-8 and MCP-1, was strongly reduced when cells were treated with statins. Immunostaining of human carotid atherosclerotic lesions of patients subjected to statin treatment revealed less CD40 expression on a ‘per vascular cell’ basis compared to control patients. Although many pleiotropic effects of statins are mediated by nitric oxide synthase (NOS)- or peroxisome proliferator-activated receptor (PPAR)-dependent signaling pathways, we observed similar statin-induced reduction of CD40 expression using NOS inhibitors or different PPAR ligands. Conclusion: Statins decrease CD40 expression and CD40-related activation of vascular cells. These effects are partially reversed by the HMG-CoA reductase product L-mevalonate and are mediated by NOS- or PPAR-dependent pathways. Altogether, these findings provide mechanistic insight into the beneficial effects of statins on atherogenesis. They also provide a scientific rationale for the use of statins as immunomodulators after organ transplantation.
KEYWORDS Atherosclerosis; Cytokines; Immunology; Lipid metabolism; Receptors
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