title: Adeno-associated virus serotype 8 ApoA-I gene transfer reduces progression of atherosclerosis in ApoE-KO mice: comparison of intramuscular and intravenous administration.
abstract: Apolipoprotein A-I (ApoA-I)/high-density lipoprotein (HDL)-raising treatments are effective antiatherosclerotic strategies. We have compared the antiatherogenic effects of human ApoA-I (hApoA-I) overexpression by intraportal and intramuscular gene transfer in atherosclerotic ApoE-knockout mice. Atherosclerotic lesions were induced by atherogenic diet. After atherosclerosis induction, a group of animals was killed and served as atherosclerosis baseline-control group. The remaining animals were randomized into the following groups: (1) atherosclerosis-progression-control, (2) intraportal/vector administration, and (3) intramuscular/vector administration. Aortas and hearts were processed for atherosclerotic quantification by en face Sudan IV and Oil Red-O, respectively. Liver and muscle specimens were processed for protein/gene expression analysis. A sustained increase in hApoA-I/HDL plasma levels was observed in both transduced groups. hApoA-I overexpression abolished plaque progression versus progression-control group. hApoA-I overexpression significantly reduced lesion macrophage, feature indicative of plaque stabilization. Scavenger receptor class-B type I (SR-BI), but not ATP-binding cassette, sub-family A (ABCA), member 1 (ABCA-1), was significantly upregulated in treated groups versus progression-controls. The results of this study show a similar effect of hApoA-I/HDL overexpression on plaque progression/stabilization by 2 different routes of administration. Our results showing similar effects using either intramuscular administration and intraportal route of administration may have significant clinical implications, given the reduced medical risk to patient and cost of intramuscular injections.
authors.affiliation: Atherothrombosis Research Unit, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cimmino
authors.forename: Chiara
authors.initials: C
authors.lastname: Giannarelli
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Matilde
authors.initials: M
authors.lastname: Alique
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Santos-Gallego
authors.forename: Valentin
authors.initials: V
authors.lastname: Fuster
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Walsh
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Badimon
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000032:analysis / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000473:pathology; D016632:Apolipoprotein A-I / Q000008:administration & dosage / Q000097:blood / Q000235:genetics* / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008076:Cholesterol, HDL / Q000097:blood; D000229:Dependovirus / Q000235:genetics / Q000378:metabolism*; D004036:Diet, Atherogenic; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D005822:Genetic Vectors; D006801:Humans; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D051122:Scavenger Receptors, Class B / Q000032:analysis / Q000235:genetics; D013997:Time Factors; D014161:Transduction, Genetic
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D008076:Cholesterol, HDL; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B