B. Degeest et al., EFFECTS OF ADENOVIRUS-MEDIATED HUMAN APO A-I GENE-TRANSFER ON NEOINTIMA FORMATION AFTER ENDOTHELIAL DENUDATION IN APO E-DEFICIENT MICE, Circulation, 96(12), 1997, pp. 4349-4356
Background Inactivation of apolipoprotein (apo) E genes in mice marked
ly increases beta-VLDL levels and accelerates progression of complex a
therosclerotic lesions. The present study investigated (1) the effect
of apo E deficiency (apo E-/-) on neointima formation after endothelia
l denudation; and (2) the effect of increased HDL, induced by adenovir
us-mediated transfer of a human apo A-I gene, on neointima formation.
Methods and Results Guidewire-induced abrasion of the endothelium of t
he 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-/- mic
e (n=12). Neointima consisted primarily of smooth muscle alpha-actin p
ositive cells. Injection in C57BL/6J apo E-/- mice of 2x10(9) (n=5) or
4x10(9) (n=7) plaque forming units (p.f.u.) of a recombinant human ap
o A-I adenovirus 3 days before injury resulted in an increase of HDL c
holesterol 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 ra
tio 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 v
ersus C57BL/6J apo E-/- mice) with 2x10(9) p.f.u. of apo A-I virus and
to 0.03+/-0.01 with 4X10(9) p.f.u. (P<.01 versus C57BL/6J apo E-/- mi
ce). Injection of 4x10(9) p.f.u. of RR5 (n=7) or tissue plasminogen ac
tivator (t-PA) control virus (n=6) did not result in a significant alt
eration of HDL cholesterol (44+/-11 and 26+/-4 mg/dL, respectively) no
r in a reduction of intima/media ratio (0.81+/-0.35 and 0.86+/-0.23, r
espectively). Conclusions Apo E deficiency is associated with increase
d neointima formation after endothelial denudation. Gene transfer of a
po A-I increases HDL cholesterol and significantly reduces neointima f
ormation, which suggests a direct vascular protective effect of HDL.