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Arteriosclerosis, Thrombosis, and Vascular Biology
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Published Online
on March 15, 2007

Arteriosclerosis, Thrombosis, and Vascular Biology. 2007
Published online before print March 15, 2007, doi: 10.1161/ATVBAHA.106.134007
A more recent version of this article appeared on June 1, 2007
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Submitted on October 13, 2006
Accepted on February 21, 2007

Grb2 Is Required for Atherosclerotic Lesion Formation

Brandon M. Proctor ; Jie Ren ; Zhouji Chen ; Jochen G. Schneider ; Trey Coleman ; Traian S. Lupu ; Clay F. Semenkovich ; and Anthony J. Muslin *

From the Center for Cardiovascular Research (B.M.P, J.R., T.S.L., A.J.M.), Division of Endocrinology, Metabolism, and Lipid Research (Z.C., J.G.S., T.C., C.F.S.), Department of Cell Biology and Physiology (B.M.P., A.J.M.); Washington University School of Medicine, St. Louis, Mo.

* To whom correspondence should be addressed. E-mail: amuslin{at}imgate.wustl.edu.

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.

Methods and 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.
Key words: atherosclerosis • Grb2 • MAPK • oxidized LDL • macrophage






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