Egr-1 deficiency in bone marrow-derived cells reduces atherosclerotic lesion formation in a hyperlipidaemic mouse model.
OBJECTIVE
Early growth response gene-1 (Egr-1) regulates the expression of genes important to cardiovascular disease. Within atherosclerotic lesions, Egr-1 is expressed in smooth muscle cells, endothelial cells, and macrophages. Since macrophages play a pivotal role in atherosclerotic lesion initiation and progression, this study investigated the effects of Egr-1 deficiency within bone marrow-derived cells on the development of atherosclerosis in a hyperlipidaemic mouse model.


RESULTS
Bone marrow from Egr-1-deficient mice and wild-type controls was transplanted into lethally irradiated LDL receptor null mice. After 26 weeks on a high fat diet, atherosclerotic lesion size within the aortic sinus of recipients was evaluated. Mice receiving Egr-1-deficient bone marrow had significantly decreased lesion size compared with controls. Lesions of these mice contained fewer macrophages and had reduced expression of vascular cell adhesion molecule-1 (VCAM-1), tissue factor, as well as transforming growth factor receptor type II, which are target genes of Egr-1. These results were validated by in vitro analysis of Egr-1-deficient peritoneal macrophages which, after lipopolysaccharide stimulation, had decreased VCAM-1 and tissue factor mRNA expression compared with wild-type controls.


CONCLUSIONS
This study demonstrates that bone marrow-derived Egr-1 promotes macrophage accumulation, atherosclerotic lesion development, and lesion complexity.
Albrecht
Claudia
C
Department of Internal Medicine III, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
Preusch
Michael R
MR
Hofmann
Götz
G
Morris-Rosenfeld
Samuel
S
Blessing
Erwin
E
Rosenfeld
Michael E
ME
Katus
Hugo A
HA
Bea
Florian
F
D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism* / Q000473:pathology; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001854:Bone Marrow Cells / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000172:deficiency* / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D006949:Hyperlipidemias / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011828:Radiation Chimera; D000077294:Receptor, Transforming Growth Factor-beta Type II; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D013925:Thromboplastin / Q000378:metabolism; D013997:Time Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D014916:Whole-Body Irradiation
D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D008055:Lipids; D012333:RNA, Messenger; D011973:Receptors, LDL; D018125:Receptors, Transforming Growth Factor beta; D019010:Vascular Cell Adhesion Molecule-1; D013925:Thromboplastin; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II