Published online before print September 11, 2008, doi: 10.1161/ATVBAHA.108.174128
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© 2008 American Heart Association, Inc.
Integrative Physiology/Experimental Medicine |
Critical Role of Macrophages in Glucocorticoid Driven Vascular Calcification in a Mouse-Model of Atherosclerosis
From the Department of Internal Medicine (M.R.P., C.A., U.M., E.B., H.A.K., F.B.), University of Heidelberg, Germany; the Department of Clinical and Experimental Medicine (M.R., G.Z., P.P.), University of Padova, Italy; the Leibniz Institute for Age Research (J.T.), Fritz-Lipman-Institute, Jena, Germany; the German Cancer Research Center (G.S.), Division of Molecular Biology of the Cell I, Heidelberg, Germany; the Department of Radiation Oncology (R.K.), Helios Klinikum Berlin-Buch, Germany; and the Department of Environmental and Occupational Health Sciences (M.E.R.), University of Washington, Seattle.
Correspondence to Florian Bea, MD, Medizinische Klinik III, Universität Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. E-mail florian.bea{at}med.uni-heidelberg.de
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 (GRLysMCre) on atherogenesis and vascular calcification in a hyperlipidemic mouse-model.
Methods and Results— Bone marrow was isolated from GRLysMCre mice and wild-type controls (GRflox) 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.
Inflammation and glucocorticoids participate in vascular calcification. The deletion of the glucocorticoid receptor in macrophages attenuated vascular calcification in mice. Bovine smooth muscle cells revealed increased calcium deposition after treatment with conditioned medium from glucocorticoid-treated macrophages. This study demonstrates that macrophages play an important role in glucocorticoid-dependent vascular calcification.
Key Words: atherosclerosis • inflammation • macrophages • glucocorticoid receptor • vascular calcification
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Arterioscler Thromb Vasc Biol 2008 28: 2096-2098.
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