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

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 ≈6× >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.