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  • 1
    Keywords: ACTIVATION, antibodies, antibody, APOLIPOPROTEIN-E, ATHEROSCLEROSIS, BLOOD, CELL, cell proliferation
    Abstract: Objective-Resident immune cells are a hallmark of atherosclerotic lesions. The sphingolipid analogue drug FTY720 mediates retrafficking of immune cells and inhibits their homing to inflammatory sites. We have evaluated the effect of FTY720 on atherogenesis and lipid metabolism. Methods and Results-ApoE(-/-) mice on a normal laboratory diet received oral FTY720 for 12 weeks, which led to a 2.4-fold increase in serum cholesterol ( largely VLDL fraction) and a 1.8-fold increase in hepatic HMGCoA reductase mRNA. FTY720 increased plasma sphingosine-1-phosphate and induced marked peripheral blood lymphopenia. A discoordinate modulation of B, T and monocyte cell numbers was found in peripheral lymphoid organs. Overall depletion of T cells was accompanied by a relative ( 2-fold) increase in regulatory T cell content paralleled by a similar increase in effector memory T cells ( CD4+CD44hiCD62lo) as absolute numbers of both subpopulations remained essentially unchanged. Lymphocyte function was unaltered as indicated by anti-OxLDL antibodies and T cell proliferation. There were no changes in atherosclerotic lesions in early and established atherosclerosis. Conclusions-FTY720 mediated peripheral lymphocyte depletion and retrafficking without altering function and overall balance of pro- and antiatherogenic lymphocyte populations. A net decrease in lymphocyte numbers occurred concomitantly with a more proatherogenic hypercholesterolemia resulting in unaltered atherogenesis
    Type of Publication: Journal article published
    PubMed ID: 17761943
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  • 2
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; CELL ; Germany ; VITRO ; DISEASE ; MICE ; TIME ; MACROPHAGES ; SERA ; REDUCTION ; animals ; bone marrow ; BONE-MARROW ; DELETION ; NO ; LESIONS ; DIFFERENCE ; inactivation ; MUSCLE ; ATHEROSCLEROSIS ; DIET ; MOUSE MODEL ; VASCULATURE ; glucocorticoid receptor ; CALCIUM ; BEHAVIOR ; SMOOTH-MUSCLE ; inflammation ; SERUM ; PRODUCTS ; INCREASE ; DEFICIENT MICE ; GC ; methods ; dexamethasone ; USA ; BONE ; animal ; SMOOTH-MUSCLE-CELLS ; smooth muscle cells ; MEDIA ; RANKL ; VASCULAR CALCIFICATION ; MUSCLE-CELLS ; MARROW ; in vitro ; CRUCIAL ROLE ; DRIVEN ; ARTERIAL CALCIFICATION ; CHOLESTEROL-FED RABBITS ; CORONARY ANGIOPLASTY ; KAPPA-B LIGAND ; OSTEOPROTEGERIN ; RECEPTOR ACTIVATOR
    Abstract: Objective - Macrophage-derived products are known to play a crucial role during atherogenesis and vascular calcification. Glucocorticoids (GC) are important modulators of immune cell functions, but their specific effects on macrophages behavior during plaque formation are not defined. The present study was therefore designed to investigate the effects of macrophage-specific deletion of the glucocorticoid receptor (GR(LysMCre)) on atherogenesis and vascular calcification in a hyperlipidemic mouse-model. Methods and Results - Bone marrow was isolated from GRLysMCre mice and wild-type controls (GR(flox)) and subsequently transplanted into lethally irradiated LDL-receptor -deficient mice. Animals were fed a Western-type diet for 15 or 24 weeks, and atherosclerotic lesions within the aortic sinus were evaluated. At both time points, no significant difference in serum lipid and corticosterone concentrations, atherosclerotic lesion size and macrophage-content within the lesions could be observed. However, GRLysMCre mice showed less calcification as well as a significant reduction of RANKL, BMP2, and Msx2 expression within the vasculature. In vitro studies using conditioned media from macrophages which had been stimulated with dexamethasone demonstrated a dose-dependent increase in calcium deposition by vascular smooth muscle cells. Conclusion - This study demonstrates that macrophage-specific glucocorticoid receptor inactivation reduces vascular calcification without affecting atherosclerotic lesion size in LDL receptor -deficient mice. (Arterioscler Thromb Vasc Biol. 2008;28:2158-2164.)
    Type of Publication: Journal article published
    PubMed ID: 18787189
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