Efficient inhibition of intimal hyperplasia by adenovirus-mediated inducible nitric oxide synthase gene transfer to rats and pigs in vivo

• Published in: Journal of the American College of Surgeons Vol. 187; no. 3; pp. 295 - 306
• Main Authors: Shears, Larry L., Kibbe, Melina R., Murdock, Alan D., Billiar, Timothy R., Lizonova, Alena, Kovesdi, Imre, Watkins, Simon C., Tzeng, Edith
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.09.1998; Elsevier Science; American College of Surgeons
• Subjects: Adenoviridae; Animals; Biological and medical sciences; Cardiovascular system; Carotid Arteries - enzymology; Carotid Arteries - pathology; Cells, Cultured; Gene Transfer Techniques; Genetic Therapy - methods; Genetic Vectors; Hyperplasia - prevention & control; Iliac Artery - enzymology; Iliac Artery - pathology; Male; Medical sciences; Muscle, Smooth, Vascular - enzymology; Muscle, Smooth, Vascular - pathology; Nitric Oxide - biosynthesis; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - genetics; Nitric Oxide Synthase Type II; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Swine; Vascular wall; Adenoviridae; Rat; Hyperplasia; Cardiovascular disease; Vascular disease; Prevention; Gene; Human adenovirus; Atherosclerosis; Intima; Vector; Ungulata; Enzyme; Rodentia; Experimental study; Nitric-oxide synthase; Pig; Virus; Restenosis; Gases; In vivo; Vertebrata; Mammalia; Animal; Mastadenovirus; Artiodactyla; Oxidoreductases
• ISSN: 1072-7515; 1879-1190
• DOI: 10.1016/S1072-7515(98)00163-X

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. Study Design: 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 × 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-N 6-(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 × 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.