ANTISENSE BASIC FIBROBLAST GROWTH-FACTOR GENE-TRANSFER REDUCES NEOINTIMAL THICKENING AFTER ARTERIAL INJURY

Purpose: To determine whether synthesis of endogenous basic fibroblast growth factor (bFGF) after arterial injury is critical to the intimal thickening response, intraluminal adenoviral gene transfer of an anti sense bFGF (Ad.ASbFGF) transgene was used to inhibit the subsequent sy nthesis of bFGF protein after injury. Methods: Sprague-Dawley rats und erwent balloon catheter carotid artery injury and in vivo gene transfe r. Isolated segments of rat common carotid artery were infected with a n adenoviral vector encoding an antisense bFGF transcript at concentra tions of 2 x 10(9), 1 x 10(10), or 1 x 10(11) pfu/ml. Control rats wer e treated with either a control adenovirus encoding the beta-galactosi dase gene, (Ad.lacZ), at 1 x 10(10), or 1 x 10(11) pfu/ml, or phosphat e-buffered saline solution (vehicle). Two weeks after injury the rats were killed and perfusion-fixed. Cross-sectional areas of the carotid arterial intima and media were measured by planimetry, and the intima/ media ratio (I/M) was calculated for each vessel. Results: The mean I/ M for each Ad.ASbFGF group and controls were compared and the signific ance assessed by analysis of variance. At two weeks after injury, the highest dose of Ad.ASbFGF, 1 x 10(11) pfu/ml, resulted in a near total inhibition of thickening (I/M = 0.14 +/- 0.04, mean +/- SEM) when com pared with phosphate-buffered saline solution alone (I/M = 0.99 +/- 0. 07), or Ad.lacZ 1 x 10(10) pfu/ml (I/M = 1.01 +/- 0.10) control treatm ents (p < 0.01). A tenfold lower dose of Ad.ASbFGF, 1 x 10(10) pfu/ml, also caused significant reduction in intimal thickening (I/M = 0.39 /- 0.07, p < 0.01). Treatment with 2 x 10(9) pfu/ml Ad.ASbFGF did not significantly limit intimal thickening (I/M = 0.72 +/- 0.12). Conclusi ons: Inhibition of bFGF synthesis in vivo using an antisense RNA strat egy significantly inhibits intimal thickening after arterial balloon i njury. This study suggests that continued bFGF synthesis contributes t o intimal thickening after arterial injury, and that antisense bFGF ma y represent an effective strategy in limiting restenosis after angiopl asty.