(Circulation. 1997;96:4349-4356.)
© 1997 American Heart Association, Inc.
Articles |
Effects of Adenovirus-Mediated Human Apo A-I Gene Transfer on Neointima Formation After Endothelial Denudation in Apo E–Deficient Mice
From the Center for Molecular and Vascular Biology, University of Leuven (Belgium).
Correspondence to D. Collen, MD, PhD, Center for Molecular and Vascular Biology, University of Leuven, Campus Gasthuisberg O&N, Herestraat 49, B-3000 Leuven, Belgium. E-mail desire.collen{at}med.kuleuven.ac.be
Background Inactivation of apolipoprotein (apo) E genes in mice markedly increases ß-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 Results Guidewire-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
-actin positive cells. Injection in C57BL/6J apo
E-/- mice of 2x109 (n=5) or
4x109 (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 2x109 p.f.u. of apo A-I virus and to 0.03±0.01 with
4x109 p.f.u. (P<.01 versus C57BL/6J apo
E-/- mice). Injection of 4x109 p.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).
Conclusions Apo 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.
Key Words: atherosclerosis • endothelial injury • lipoproteins • apolipoproteins
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