Low-dose FK506 blocks collar-induced atherosclerotic plaque development and stabilizes plaques in ApoE-/- mice.
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 (approximately 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.
Donners
Marjo M P C
MM
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, the Netherlands.
Bot
Ilze
I
De Windt
Leon J
LJ
van Berkel
Theo J C
TJ
Daemen
Mat J A P
MJ
Biessen
Erik A L
EA
Heeneman
Sylvia
S
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects; D001161:Arteriosclerosis / Q000473:pathology / Q000517:prevention & control*; D001772:Blood Cell Count; D004195:Disease Models, Animal; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008156:Luciferases / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D058225:Plaque, Amyloid / Q000473:pathology*; D016559:Tacrolimus / Q000008:administration & dosage*
D001057:Apolipoproteins E; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D008156:Luciferases; D016559:Tacrolimus