Sustained decrease in superoxide dismutase activity underlies constrictive remodeling after balloon injury in rabbits

Objective - The redox pathophysiology of vascular repair is incompletely understood. We assessed the role of vascular superoxide dismutase (SOD) activity in oxidative/nitrative stress and caliber loss postinjury (PI). Methods and Results - Rabbits submitted to iliac artery balloon overdistension were followed for 14 days PI. Significant decrease in vascular SOD activity occurred at 7 and 14 days PI (by 45% and 34%, respectively, versus control, 96 +/- 1 U/mg, P < 0.05). Separation in concanavalin-A column showed that both extracellular SOD (ecSOD) and CuZn SOD activities were reduced, whereas Western analysis showed normal or augmented protein expression. Immunoreactivity to nitrotyrosine, neuronal NO synthase ( NOS), and inducible NOS ( iNOS) increased in media and neointima PI; iNOS mRNA also augmented. Administration of ecSOD from days 7 to 14 PI corrected the SOD activity decrease and minimized caliber loss by 59% (P = 0.007) despite unaltered neointima. Nitrate levels markedly increased with ecSOD in injured artery homogenates (26 +/- 5 versus 4 +/- 0.3 μmol/ L per mg, P = 0.001). Such increase was 70% inhibited by specific iNOS antagonist 1400w. Nitrotyrosine and neuronal NOS expression decreased after ecSOD. Conclusions - Sustained low vascular SOD activity has a key role in constrictive remodeling after injury, promoting oxidative/ nitrative stress and impairment of iNOS-derived NO bioavailability. SOD function may critically determine whether iNOS induction is beneficial or deleterious in vivo.