Inhibitory Effect of Inducible Nitric Oxide Synthase Gene Transfer on Intimal Hyperplasia and Fibronectin Expression Induced by Carotid Artery Denudation

Kye, Bong Hyeon; Hong, Sun Young; Yang, Keun Ho; Park, Sun Cheol; Park, Jang Sang

Abstract

PURPOSE
Intimal hyperplasia is a pathologic condition that is commonly observed with the atherosclerotic change of blood vessels; this condition is usually observed after arterial operation and interventions such as angioplasty, endaterectomy and bypass grafting, and it remains a major cause for hindering for arterial patency. It is a multiple processes that includes smooth muscle cell migration, proliferation, and expression of extracellular matrix proteins, such as fibronectin. Nitric oxide (NO) has been found to possess many different vasoprotective properties: inhibition of platelet aggregation and adherence, inhibition of leukocyte chemotaxis, inhibition of vascular smooth muscle cell proliferation and migration, inhibition of endothelial cell apoptosis and stimulation of endothelial cell growth. Overexpression of nitric oxide synthase (NOS) in the vascular wall has been used to regulate vasomotor function, prevent neointimal formation after balloon injury or vein grafting, and to prevent transplant vasculopathy. NOS gene transfer to the vascular wall holds great promise as a means of controlling local vascular function. METHOD: We investigated whether the inducible NOS (iNOS) gene transfer to the arterial wall has an inhibitory effect on intimal hyperplasia after endothelial denudation and on the change of the level of extracellular matrix fibronectin expression in the rabbit common carotid artery. Rabbits were divided into three groups: the saline only (without injury) normal group, the injury + saline intima injury group, and the injury + recombinant adenoviral vector encording human iNOS (AdiNOS) gene transfer group (n=5 per group). AdiNOS (1.6x10(10) plaque-forming units [pfu]) were used for the iNOS gene delivery and the virus was intraluminally infected to the balloon-injured common carotid arterial wall for 20 minutes. The NO levels were assessed in the blood of all the animals at the three time point: before-, 1 hr after-, and 14 days after the surgical procedures. The left common carotid arteries were harvested from the animals at 14 days after balloon injury and they were then assessed for fibronectin expression and intimal hyperplasia. RESULT: 14 days after AdiNOS infection, the NO levels were increased 67% in the gene transfer group compared with those levels obtained before the gene transfer (333.5+/-11.5 vs. 557.4+/-72.1, respectively, P<0.05), and the intima/intima+media ratio and the FN expression were reduced by 60% and 50%, respectively, in the gene transfer group compared with the intima injury group (41.5+/-5.6 vs. 16.6+/-2.8, respectively, P<0.05 and 307.9+/-38.3 vs. 154.3+/-20.2, respectively, P<0.05).
CONCLUSION
Our results show that iNOS gene transfer to the arterial wall resulted in increased NO levels in the blood, and the procedure greatly inhibited intimal hyperplasia and it reduced fibronectin expression in the arteriaql wall.