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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1460.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Subphysiologic Apolipoprotein E (ApoE) Plasma Levels Inhibit Neointimal Formation After Arterial Injury in ApoE-Deficient Mice

Hilke Wientgen; Fayanne E. Thorngate; Sabina Omerhodzic; Linda Rolnitzky; John T. Fallon; David L. Williams; Edward A. Fisher

From the Departments of Medicine (E.A.F.)/Division of Endocrinology (H.W.), and Biomathematics/Biostatistics (L.R.), and Pathology (J.T.F.), and the Zena and Michael A. Wiener Cardiovascular Institute (S.O., J.T.F., E.A.F.), Mount Sinai School of Medicine, New York, NY; the Department of Pharmacological Sciences (F.E.T., D.L.W.), State University of New York at Stony Brook, Stony Brook, NY; and the Department of Medicine, the Leon H. Charney Division of Cardiology and the Marc and Ruti Bell Program in Vascular Biology (E.A.F.), New York University School of Medicine, New York, NY.

Correspondence to Edward A. Fisher, MD, PhD, New York University School of Medicine, 550 First Ave, TH-451, New York, NY 10016. E-mail edward.fisher{at}med.nyu.edu

Objective— Apolipoprotein E (apoE) reduces mouse atherosclerosis progression independent of plasma cholesterol level effects. A mouse artery injury model was used to examine whether apoE exhibits beneficial lipid-independent effects on neointimal formation.

Methods and Results— ApoE-deficient (apoE–/–), wild-type (WT), and transgenic apoE–/– mice (secreting apoE at different levels from adrenal glands) underwent femoral artery injury. Mice with low expression of plasma apoE (0.1% of WT) had cholesterol levels approximately half those of apoE–/– littermates (but still 6x >WT). Mice with higher expression (HE; 2% to 3% of WT) of plasma apoE had cholesterol levels approximately twice those of WT. Injured WT mouse (versus apoE–/–) arteries had a smaller mean intima-to-media (I/M) ratio (0.87 versus 1.96; P<0.05). HE mice tended to have lower mean I/M ratios (1.3; P>0.05 versus apoE–/– mice). Multiple regression analysis indicated that apoE levels were significantly associated with reduced I/M ratios, but plasma cholesterol levels were not, before or after adjusting for apoE. In addition, foam cell content of the neointima and media of injured arteries, a negative prognostic indicator in postangioplasty human lesions, was inversely related to plasma apoE levels.

Conclusions— Similar to its effects on atherosclerosis progression, in a mouse model of restenosis, a subphysiological level of apoE was associated with beneficial effects on lesion size/composition.

Using transgenic mice expressing different levels of plasma apoE, we have shown that after arterial injury, subphysiological apoE levels were associated with reduced intima-to-media (I/M) ratios of lesions. Lipid levels were not associated with reduced I/M ratios, consistent with previous mouse studies of apoE and atherosclerosis progression.

Key Words: apolipoprotein E • arterial injury • neointimal formation • restenosis • mouse

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