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Low‐Dose FK506 Blocks Collar‐Induced Atherosclerotic Plaque Development and Stabilizes Plaques in ApoE−/− Mice
Author(s) -
Donners Marjo M. P. C.,
Bot Ilze,
De Windt Leon J.,
Van Berkel Theo J. C.,
Daemen Mat J. A. P.,
Biessen Erik A. L.,
Heeneman Sylvia
Publication year - 2005
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/j.1600-6143.2005.00821.x
Subject(s) - medicine , apolipoprotein e , in vivo , nfat , apoptosis , flow cytometry , pathology , calcineurin , endocrinology , immunology , transplantation , biology , disease , biochemistry , microbiology and biotechnology
Since atherosclerosis is a chronic inflammatory disease, we tested the hypothesis that the immunosuppressive drug FK506 would attenuate the development of atherosclerosis using a mouse model of collar‐induced atherosclerosis. ApoE−/− mice were treated for 4 weeks with the immunosuppressive drug FK506 (0.05 mg/kg/day), yielding sustained blood levels (∼0.2 ng/mL) without systemic side effects. Atherosclerotic plaque development of FK506‐treated mice was significantly reduced (63%) while plaque cell density was increased (52%) compared to controls. Importantly, FK506 also blocked progression of pre‐existing atherosclerotic plaques. Plaque area of pre‐existing plaques was 35% reduced by FK506. Cell density (35%) and collagen content (51%) were significantly increased, whereas necrotic core content was decreased (42%), indicating a more stable plaque morphology. Similar results were found during spontaneous atherosclerotic plaque development in ApoE−/− mice (treatment 17–25 weeks of age). Flow‐cytometric analysis showed no peripheral effects on blood cell count or T‐cell activation after FK506‐treatment. In vitro , FK506 decreased vascular smooth muscle cell (VSMC) apoptosis and inhibited nuclear factor of activated T cells (NFAT)‐luciferase reporter activity at concentrations in the range of the in vivo concentration.Low‐dose FK506 inhibits collar‐induced atherosclerotic plaque development and progression and induces more stable plaque phenotypes in ApoE−/− mice without any peripheral side effects.