Local resistance to oxidative stress by overexpression of copper-zinc superoxide dismutase limits neointimal formation after angioplasty

Purpose: To examine the effects of oxidative stress on neointimal hyperplasia through local overexpression of human copper-zinc superoxide dismutase (Cu-Zn SOD). Methods: The left common femoral arteries (CFA) of 18 New Zealand white rabbits were subjected to balloon overdilation injury. Each dilated CFA was then incubated with either a nonviral (buffer) or viral (adenovirus overexpressing β-galactosidase) control or an adenovirus overexpressing Cu-Zn SOD. Animals were then sacrificed at 3, 7, or 28 days (3 arteries per group per time point) and the treated CFA segments were harvested for analysis of esterase-positive inflammatory cells and extracellular matrix elements. The intima-to-media ratio (I/M) was measured to assess the degree of neointimal formation. Results: At 3 days, local SOD levels in the Cu-Zn SOD-treated group were significantly elevated relative to both controls (p<0.01). Significant reductions in lipid peroxidation by-products were also seen in the SOD group relative to viral and nonviral controls (p<0.05). Mean I/M at 28 days was 0.582±0.088 for the nonviral control group versus 0.565±0.133 for the viral control group. The SOD-treated group had a significant reduction relative to both controls: 0.259±0.045 (p<0.05). Statistically significant reductions in I/M were also demonstrated in the SOD group relative to control groups at 7 days (p<0.05). The SOD-treated group demonstrated significant preservation of elastin relative to controls, as well as a significant reduction in esterase-positive granulocytes relative to controls (p<0.05). Conclusions: Direct buffering of oxidative stress in balloon-injured vessels can significantly alter postinjury response and limit neointimal hyperplasia.