title: Efficient inhibition of intimal hyperplasia by adenovirus-mediated inducible nitric oxide synthase gene transfer to rats and pigs in vivo.
abstract: BACKGROUND
  Inadequate nitric oxide (NO) availability may underlie vascular smooth muscle overgrowth that contributes to vascular occlusive diseases including atherosclerosis and restenosis. NO possesses a number of properties that should inhibit this hyperplastic healing response, such as promoting reendothelialization, preventing platelet and leukocyte adherence, and inhibiting cellular proliferation.
  
  
  METHODS
  We proposed that shortterm but sustained increases in NO synthesis achieved with inducible NO synthase (iNOS) gene transfer at sites of vascular injury would prevent intimal hyperplasia. We constructed an adenoviral vector, AdiNOS, carrying the human iNOS cDNA and used it to express iNOS at sites of arterial injury in vivo.
  
  
  RESULTS
  AdiNOS-treated cultured vascular smooth muscle cells produced up to 100-fold more NO than control cells. In vivo iNOS gene transfer, using low concentrations of AdiNOS (2 x 10(6) plaque forming units [PFU]/rat) to injured rat carotid arteries, resulted in a near complete (>95%) reduction in neointima formation even when followed longterm out to 6 weeks post-injury. This protective effect was reversed by the continuous administration of an iNOS selective inhibitor L-N6-(1-iminoethyl)-lysine. However, iNOS gene transfer did not lead to regression of preestablished neointimal lesions. In an animal model more relevant to human vascular healing, iNOS gene transfer (5 x 10(8) PFU/pig) to injured porcine iliac arteries in vivo was also efficacious, reducing intimal hyperplasia by 51.8%.
  
  
  CONCLUSIONS
  These results indicate that shortterm overexpression of the iNOS gene initiated at the time of vascular injury is an effective method of locally increasing NO levels to prevent intimal hyperplasia.
authors.affiliation: University of Pittsburgh, Department of Surgery, PA 15261, USA.
authors.forename: L L
authors.initials: LL
authors.lastname: Shears
authors.forename: M R
authors.initials: MR
authors.lastname: Kibbe
authors.forename: A D
authors.initials: AD
authors.lastname: Murdock
authors.forename: T R
authors.initials: TR
authors.lastname: Billiar
authors.forename: A
authors.initials: A
authors.lastname: Lizonova
authors.forename: I
authors.initials: I
authors.lastname: Kovesdi
authors.forename: S C
authors.initials: SC
authors.lastname: Watkins
authors.forename: E
authors.initials: E
authors.lastname: Tzeng
mesh_terms: D000256:Adenoviridae; D000818:Animals; D002339:Carotid Arteries / Q000201:enzymology / Q000473:pathology; D002478:Cells, Cultured; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006965:Hyperplasia / Q000517:prevention & control*; D007083:Iliac Artery / Q000201:enzymology / Q000473:pathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000473:pathology*; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine
chemical_list: D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat