title: Gene transfer of endothelial NO synthase, but not eNOS plus inducible NOS, regressed atherosclerosis in rabbits.
abstract: The effects of in vivo gene transfer of endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) genes on severe atherosclerosis were investigated in rabbits. The recombinant adenoviruses, Ad.eNOS and Ad.iNOS, which respectively express eNOS and iNOS, were constructed. Atherosclerosis was induced by a balloon injury followed by a high cholesterol diet for 12 weeks. The rabbits were divided into six groups: Gp cont (no treatment); Gp null (adenovirus sham-infected); Gp eNOS (Ad.eNOS); Gp iNOS (Ad.iNOS); Gp e+i (Ad.eNOS plus Ad.iNOS); and Gp heNOS (a high dose of Ad.eNOS). Examinations were carried out 7 days after gene transfer. Plasma lipid levels were not significantly changed, but transfection with Ad.eNOS (Gp eNOS and Gp heNOS) decreased the tissue cholesterol concentration and regressed atherosclerotic lesions. Vessels treated with Ad.iNOS (Gp iNOS and Gp e+i) showed iNOS staining in the atheroma, and slight staining at other parts of the vessels; those treated with Ad.eNOS showed eNOS staining in the endothelium and subintima, and slight staining at other parts. Ad.eNOS transfection, but not Ad.iNOS or Ad.eNOS+Ad.iNOS transfection, improved the impaired aortic endothelium-dependent relaxation (EDR) and basal NO-dependent response, increased tissue cyclic GMP (cGMP), and decreased the release of O2- from vessels. eNOS treatment showed a decreasing tendency in regions with peroxynitrite staining, MMP1 staining, and suspected apoptosis. In conclusion, in vivo gene transfer of eNOS, but not iNOS or eNOS plus iNOS, regressed atherosclerosis. The relations among NO, O2-, and peroxynitrite may be critical, and lipid resorption from the lesions may be responsible for the regression.
authors.affiliation: Department of Geriatrics, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa, Nagoya 466-8550, Japan. hayashi@med.nagoya-u.ac.jp
authors.forename: Toshio
authors.initials: T
authors.lastname: Hayashi
authors.forename: Daigo
authors.initials: D
authors.lastname: Sumi
authors.forename: Packiasamy A R
authors.initials: PA
authors.lastname: Juliet
authors.forename: Hisako
authors.initials: H
authors.lastname: Matsui-Hirai
authors.forename: Yukako
authors.initials: Y
authors.lastname: Asai-Tanaka
authors.forename: Hatsuyo
authors.initials: H
authors.lastname: Kano
authors.forename: Akiko
authors.initials: A
authors.lastname: Fukatsu
authors.forename: Taku
authors.initials: T
authors.lastname: Tsunekawa
authors.forename: Asaka
authors.initials: A
authors.lastname: Miyazaki
authors.forename: Akihisa
authors.initials: A
authors.lastname: Iguchi
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Ignarro
mesh_terms: D000109:Acetylcholine; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism / Q000473:pathology; D001161:Arteriosclerosis / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002784:Cholesterol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D007261:Infusions, Intra-Arterial; D050356:Lipid Metabolism; D008297:Male; D023421:Models, Animal; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D005996:Nitroglycerin; D010100:Oxygen / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism; D011817:Rabbits; D014161:Transduction, Genetic / Q000379:methods*; D014665:Vasodilator Agents; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; D030421:Peroxynitrous Acid; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D002784:Cholesterol; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D005996:Nitroglycerin; D000109:Acetylcholine; D010100:Oxygen