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 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.