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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1361.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

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; 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.

Correspondence to Dr. Anthony J. Muslin, Center for Cardiovascular Research, Washington University School of Medicine, 660 South Euclid Avenue, Box 8086, St. Louis, MO 63110. 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.

We tested the role of Grb2 in atherosclerosis using Grb2^+/– apoE^–/– mice. Grb2^+/– apoE^–/– mice were resistant to atherosclerosis, and Grb2 haploinsufficiency in blood-borne cells conferred resistance to lesion formation. Also, Grb2 was required for foam cell formation. These results implicate a fundamental role for Grb2 in atherosclerotic lesion formation.

Key Words: atherosclerosis • Grb2 • MAPK • oxidized LDL • macrophage

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