Critical role of macrophages in glucocorticoid driven vascular calcification in a mouse-model of atherosclerosis.
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.


RESULTS
Bone marrow was isolated from GR(LysMCre) 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, GR(LysMCre) 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.


CONCLUSIONS
This study demonstrates that macrophage-specific glucocorticoid receptor inactivation reduces vascular calcification without affecting atherosclerotic lesion size in LDL receptor-deficient mice.
Preusch
Michael R
MR
Department of Internal Medicine, University of Heidelberg, Geidelberg, Germany.
Rattazzi
Marcello
M
Albrecht
Claudia
C
Merle
Uta
U
Tuckermann
Jan
J
Schütz
Günther
G
Blessing
Erwin
E
Zoppellaro
Giacomo
G
Pauletto
Paolo
P
Krempien
Robert
R
Rosenfeld
Michael E
ME
Katus
Hugo A
HA
Bea
Florian
F
D000818:Animals; D050197:Atherosclerosis / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D016026:Bone Marrow Transplantation; D002114:Calcinosis / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005938:Glucocorticoids / Q000502:physiology*; D006949:Hyperlipidemias / Q000150:complications / Q000235:genetics; D008264:Macrophages / Q000473:pathology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000172:deficiency / Q000235:genetics; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics
D005938:Glucocorticoids; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D011973:Receptors, LDL; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D002118:Calcium