Effects of adenovirus-mediated human apo A-I gene transfer on neointima formation after endothelial denudation in apo E-deficient mice.
BACKGROUND
Inactivation of apolipoprotein (apo) E genes in mice markedly increases beta-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.


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 alpha-actin positive 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 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 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-/- mice). Injection of 4x10(9) 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.
De Geest
B
B
Center for Molecular and Vascular Biology, University of Leuven, Belgium.
Zhao
Z
Z
Collen
D
D
Holvoet
P
P
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics*; D001057:Apolipoproteins E / Q000172:deficiency*; D008076:Cholesterol, HDL / Q000097:blood; D004730:Endothelium, Vascular / Q000502:physiology*; D018014:Gene Transfer Techniques; D006801:Humans; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D011995:Recombination, Genetic / Q000502:physiology; D017539:Tunica Intima / Q000502:physiology*
D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D008055:Lipids; D008074:Lipoproteins