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Statins (HMG-CoA reductase inhibitors) reduce CD40 expression in human vascular cells


Mulhaupt, F (2003). Statins (HMG-CoA reductase inhibitors) reduce CD40 expression in human vascular cells. Cardiovascular Research, 59(3):755-766.

Abstract

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-γ-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

Abstract

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-γ-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

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Item Type:Journal Article, refereed, original work
Communities & Collections:National licences > 142-005
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Life Sciences > Physiology
Health Sciences > Cardiology and Cardiovascular Medicine
Health Sciences > Physiology (medical)
Language:English
Date:1 September 2003
Deposited On:10 Oct 2018 11:06
Last Modified:31 Jul 2020 02:10
Publisher:Oxford University Press
ISSN:0008-6363
OA Status:Hybrid
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/s0008-6363(03)00515-7
Related URLs:https://www.swissbib.ch/Search/Results?lookfor=nationallicenceoxford101016S0008636303005157 (Library Catalogue)

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