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(Circulation. 2008;117:3227-3237.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

P-Selectin Glycoprotein Ligand-1 Is Highly Expressed on Ly-6C^hi Monocytes and a Major Determinant for Ly-6C^hi Monocyte Recruitment to Sites of Atherosclerosis in Mice

Guangyu An, MD, PhD^*; Huan Wang, MD, PhD^*; Rong Tang, MD, PhD; Tadayuki Yago, MD, PhD; J. Michael McDaniel, MS; Samuel McGee, BS; Yuqing Huo, MD, PhD; Lijun Xia, MD, PhD

From the Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City (G.A., T.Y., J.M.M., S.M., L.X.); Department of Medicine, University of Minnesota Medical School, Minneapolis (H.W., R.T., Y.H.); and Department of Biochemistry and Molecular Biology and Oklahoma Center for Medical Glycobiology, University of Oklahoma Health Sciences Center, Oklahoma City (L.X.).

Correspondence to Lijun Xia, MD, PhD, Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, 825 NE 13th St, Oklahoma City, OK 73104 (e-mail Lijun-Xia{at}omrf.org) or Yuqing Huo, MD, PhD, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN 55455 (e-mail yuqing@umn.edu).

Received February 3, 2008; accepted April 14, 2008.

Background— Ly-6C^hi monocytes are key contributors to atherosclerosis in mice. However, the manner in which Ly-6C^hi monocytes selectively accumulate in atherosclerotic lesions is largely unknown. Monocyte homing to sites of atherosclerosis is primarily initiated by rolling on P- and E-selectin expressed on endothelium. We hypothesize that P-selectin glycoprotein ligand-1 (PSGL-1), the common ligand of P- and E-selectin on leukocytes, contributes to the preferential homing of Ly-6C^hi monocytes to atherosclerotic lesions.

Methods and Results— To test this hypothesis, we examined the expression and function of PSGL-1 on Ly-6C^hi and Ly-6C^lo monocytes from wild-type mice, ApoE^–/– mice, and mice lacking both ApoE and PSGL-1 genes (ApoE^–/–/PSGL-1^–/–). We found that Ly-6C^hi monocytes expressed a higher level of PSGL-1 and had enhanced binding to fluid-phase P- and E-selectin compared with Ly-6C^lo monocytes. Under in vitro flow conditions, more Ly-6C^hi monocytes rolled on P-, E-, and L-selectin at slower velocities than Ly-6C^lo cells. In an ex vivo perfused carotid artery model, Ly-6C^hi monocytes interacted preferentially with atherosclerotic endothelium compared with Ly-6C^lo monocytes in a PSGL-1–dependent manner. In vivo, ApoE^–/– mice lacking PSGL-1 had impaired Ly-6C^hi monocyte recruitment to atherosclerotic lesions. Moreover, ApoE^–/–/PSGL-1^–/– mice exhibited significantly reduced monocyte infiltration in wire injury–induced neointima and in atherosclerotic lesions. ApoE^–/–/PSGL-1^–/– mice also developed smaller neointima and atherosclerotic plaques.

Conclusions— These data indicate that PSGL-1 is a new marker for Ly-6C^hi monocytes and a major determinant for Ly-6C^hi cell recruitment to sites of atherosclerosis in mice.

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