title: Gene transfer of endothelial nitric oxide synthase reduces angiotensin II-induced endothelial dysfunction.
abstract: Angiotensin II stimulates vascular NADPH oxidase to produce superoxide, which can react with nitric oxide and impair vasomotor function. We tested the hypothesis that the overexpression of endothelial nitric oxide synthase (eNOS) or superoxide dismutase (SOD) would correct angiotensin II-induced endothelial dysfunction. We examined the effects of the gene transfer of eNOS or 2 isoforms of SOD to the aorta in angiotensin II-treated rabbits on vasomotor function. New Zealand White rabbits were treated for 1 week with angiotensin II (100 ng. kg(-1). min(-1)) or saline by osmotic minipumps. In angiotensin II-treated rabbits, mean blood pressure was 107+/-8 mm Hg; it was 67+/-5 mm Hg in saline-infused rabbits (P<0.05). In aortas from angiotensin II-treated rabbits, lucigenin-enhanced chemiluminescence demonstrated a 2.5-fold increase in superoxide levels, and the oxidative fluorescent probe hydroethidine indicated increased superoxide levels throughout the vascular wall, especially in the endothelium and adventitia. Maximal relaxation to acetylcholine was less in aortas from rabbits treated with angiotensin II (72+/-5% versus 87+/-4% in saline-treated rabbits; P<0.01), but responses to sodium nitroprusside were similar. Segments of the thoracic aorta were incubated in vitro with an adenoviral vector that expressed eNOS, copper zinc SOD (CuZnSOD), extracellular SOD (ECSOD), or beta-galactosidase. beta-Gal treatment with adenovirus containing the gene for eNOS (AdeNOS) but not adenovirus containing the gene for beta-gal (Adbeta-gal) (control virus) restored responses to acetylcholine (82+/-3% after AdeNOS and 67+/-4% after Adbeta-gal). Gene transfer of CuZnSOD or ECSOD did not improve the endothelium-dependent relaxation of the aorta in rabbits that received angiotensin II. Thus, gene transfer of eNOS, but not SOD, effectively restores vasomotor function in angiotensin II-infused rabbits.
authors.affiliation: Departments of Internal Medicine and Pharmacology, Cardiovascular Center, University of Iowa College of Medicine, Iowa City 52242, USA.
authors.forename: H
authors.initials: H
authors.lastname: Nakane
authors.forename: F J
authors.initials: FJ
authors.lastname: Miller
authors.forename: F M
authors.initials: FM
authors.lastname: Faraci
authors.forename: K
authors.initials: K
authors.lastname: Toyoda
authors.forename: D D
authors.initials: DD
authors.lastname: Heistad
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D018014:Gene Transfer Techniques; D007260:Infusion Pumps; D008297:Male; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D013482:Superoxide Dismutase / Q000235:genetics / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects / Q000235:genetics / Q000502:physiology
chemical_list: D011993:Recombinant Fusion Proteins; D013481:Superoxides; D000804:Angiotensin II; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D013482:Superoxide Dismutase