Grb2 is required for atherosclerotic lesion formation.
OBJECTIVE
Grb2 is a ubiquitously expressed linker protein that couples growth factor receptor activation to downstream mitogen-activated protein kinase (MAPK) cascades. Macrophage proliferation and uptake of modified lipoproteins are critical components of atherogenesis which require MAPK activation. However, the precise role of upstream signaling factors and the interrelationship of various MAPK cascades in the pathogenesis of atherosclerosis remains uncertain. Complete deletion of Grb2 in mice results in early embryonic lethality. However, Grb2 heterozygous mice appear normal at birth. To test the role of the Grb2 adapter protein in atherosclerotic lesion formation, we generated Grb2+/- mice in the apoE-/- genetic background.


RESULTS
Grb2+/- apoE-/- and apoE-/- mice exhibited similar body weight and serum lipid profiles. However, Grb2+/- apoE-/- mice on a Western diet had reduced lesion formation compared with apoE-/- mice by aortic sinus and en face assays. Transplantation of apoE-/- mice with Grb2+/- apoE-/- or apoE-/- bone marrow indicated that Grb2 haploinsufficiency in blood-borne cells confers resistance to Western diet-induced atherosclerosis. Cell culture experiments with bone marrow-derived macrophages showed that Grb2 is required for oxidized low density lipoprotein (oxLDL)-induced MAPK activation and foam cell formation.


CONCLUSIONS
Grb2 is required for atherosclerotic lesion formation and uptake of oxidized LDL by macrophages.
Proctor
Brandon M
BM
Center for Cardiovascular Research, Washington University School of Medicine, 660 South Euclid Avenue, Box 8086, St. Louis, MO 63110, USA.
Ren
Jie
J
Chen
Zhouji
Z
Schneider
Jochen G
JG
Coleman
Trey
T
Lupu
Traian S
TS
Semenkovich
Clay F
CF
Muslin
Anthony J
AJ
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001786:Blood Glucose / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D004041:Dietary Fats; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005487:Foam Cells / Q000378:metabolism; D051380:GRB2 Adaptor Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008055:Lipids / Q000097:blood; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*
D001057:Apolipoproteins E; D001786:Blood Glucose; D004041:Dietary Fats; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D008055:Lipids; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D020928:Mitogen-Activated Protein Kinases