title: Critical role of macrophages in glucocorticoid driven vascular calcification in a mouse-model of atherosclerosis.
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.
  
  
  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.
authors.affiliation: Department of Internal Medicine, University of Heidelberg, Geidelberg, Germany.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Preusch
authors.forename: Marcello
authors.initials: M
authors.lastname: Rattazzi
authors.forename: Claudia
authors.initials: C
authors.lastname: Albrecht
authors.forename: Uta
authors.initials: U
authors.lastname: Merle
authors.forename: Jan
authors.initials: J
authors.lastname: Tuckermann
authors.forename: Günther
authors.initials: G
authors.lastname: Schütz
authors.forename: Erwin
authors.initials: E
authors.lastname: Blessing
authors.forename: Giacomo
authors.initials: G
authors.lastname: Zoppellaro
authors.forename: Paolo
authors.initials: P
authors.lastname: Pauletto
authors.forename: Robert
authors.initials: R
authors.lastname: Krempien
authors.forename: Michael E
authors.initials: ME
authors.lastname: Rosenfeld
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Florian
authors.initials: F
authors.lastname: Bea
mesh_terms: 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
chemical_list: 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