Low- but not high-dose FK506 treatment confers atheroprotection due to alternative macrophage activation and unaffected cholesterol levels

Lili Bai; Karen Gabriels; Erwin Wijnands; Mat Rousch; Mat J. A. P. Daemen; J. W. Cohen Tervaert; Erik A. L. Biessen; Sylvia Heeneman

doi:10.1160/TH09-07-0502

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2010; 104(01): 143-150
DOI: 10.1160/TH09-07-0502

Cardiovascular Biology and Cell Signalling

Schattauer GmbH

Low- but not high-dose FK506 treatment confers atheroprotection due to alternative macrophage activation and unaffected cholesterol levels

Lili Bai^*

¹Experimental Vascular Pathology group, Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands

,

Karen Gabriels^*

¹Experimental Vascular Pathology group, Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands

,

Erwin Wijnands

¹Experimental Vascular Pathology group, Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands

,

Mat Rousch

¹Experimental Vascular Pathology group, Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands

,

Mat J. A. P. Daemen

¹Experimental Vascular Pathology group, Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands

,

J. W. Cohen Tervaert

²Department of Internal Medicine, Division of Clinical and Experimental Immunology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands

,

Erik A. L. Biessen

¹Experimental Vascular Pathology group, Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands

³Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Gorlaeus Laboratories, Leiden, The Netherlands

,

Sylvia Heeneman

¹Experimental Vascular Pathology group, Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands

› Author Affiliations

Abstract

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Summary

Previous studies showed both proand anti-atherogenic effects of immunosuppressant drug FK506 on atherosclerosis. As these divergent/paradoxical results of FK506 may at least in part be attributable to differences in FK506 dosing, we have, in the current study, assessed dosedependent effects of FK506 on atherosclerotic lesion formation as well as on inflammatory parameters relevant to atherosclerosis. Unlike low-dose FK506, high-dose FK506 did not protect against atherosclerosis in ApoE-/mice. The high-dose induced hypercholesterolaemia, whereas the low-dose did not. Both lowand high-dose FK506 treatment significantly reduced systemic CD3⁺ and CD4⁺CD25⁺ T-cell populations, and showed similar suppression of FoxP3 regulatory T-cell populations. Increased IL-4+ CD4+ T-cells and decreased IgG-MDA-LDL antibody titres pointed to a selective, albeit modest Th2 skewing in the high-dose treatment group, despite the advanced stage of atherosclerosis. Low concentrations of FK506, however, skewed bone marrow-derived macrophage polarisation towards a M2 macrophage phenotype, whereas high concentration did not. A low-dose FK506 treatment regime protected against atherosclerosis by suppressing T-cell activation and favouring (M2) macrophage polarisation. Although a high-dose FK506 treatment effected a similar T-cell suppressive effect, with an even more pronounced shift towards Th2 type immune responses, this did not translate in atheroprotection due to the hypercholesterolaemia and absent M2 skewing.

Keywords

Atherosclerosis - FK506 - immunosuppression - NFAT

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References

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