Effects of Adenovirus-Mediated Human Apo A-I Gene Transfer on Neointima Formation After Endothelial Denudation in Apo E–Deficient Mice

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Abstract
BackgroundInactivation of apolipoprotein (apo) E genes in mice markedly increases β-VLDL levels and accelerates progression of complex atherosclerotic lesions. The present study investigated (1) the effect of apo E deficiency (apo E-/-) on neointima formation after endothelial denudation; and (2) the effect of increased HDL, induced by adenovirus-mediated transfer of a human apo A-I gene, on neointima formation.Methods and ResultsGuidewire-induced abrasion of the endothelium of the common carotid artery did not produce neointima formation within 18 days after injury in C57BL/6J mice (n=12) but was associated with an intima/media ratio of 0.82±0.25 in age-matched C57BL/6J apo E−/−mice (n=12). Neointima consisted primarily of smooth muscle α-actin positive cells. Injection in C57BL/6J apo E−/−mice of 2×109(n=5) or 4×109(n=7) plaque forming units (p.f.u.) of a recombinant human apo A-I adenovirus 3 days before injury resulted in an increase of HDL cholesterol from 36±5 to 75±3 mg/dL (P<.05) and to 96±13 mg/dL (P<.05), respectively, and of the HDL cholesterol/non–HDL cholesterol ratio from 0.063±0.003 to 0.15±0.01 (P<.05) and to 0.16±0.015 (P<.05), respectively. Intima/media ratio decreased to 0.28±0.06 (P=NS versus C57BL/6J apo E−/−mice) with 2×109p.f.u. of apo A-I virus and to 0.03±0.01 with 4×109p.f.u. (P<.01 versus C57BL/6J apo E−/−mice). Injection of 4×109p.f.u. of RR5 (n=7) or tissue plasminogen activator (t-PA) control virus (n=6) did not result in a significant alteration of HDL cholesterol (44±11 and 26±4 mg/dL, respectively) nor in a reduction of intima/media ratio (0.81±0.35 and 0.86±0.23, respectively).ConclusionsApo E deficiency is associated with increased neointima formation after endothelial denudation. Gene transfer of apo A-I increases HDL cholesterol and significantly reduces neointima formation, which suggests a direct vascular protective effect of HDL.