Abstract 596: Superoxide Dismutase Mimetic AEOL 10113 Reduces Oxidative Stress, Promotes Re-endothelization and Inhibits Instent Restenosis in WHHL-rabbit Arteries
Drug-eluting stents (DES) have significantly reduced the needs for target vessel revascularization after angioplasty and stenting of coronary arteries. This is due to effective inhibition of smooth muscle cell (SMC) growth, the most prominent feature in instent restenosis. However, the delayed healing of protective endothelial cell (EC) layer associated with DES predisposes to late thrombotic events. Hence the strategies for improving the endothelial recovery while inhibiting SMC growth are warranted. The oxidative stress caused by stenting is known to promote EC apoptosis as well as SMC proliferation and is therefore a promising target for drug therapy. We studied the efficacy of a manganese metalloporphyrin AEOL 10113, a strong catalytic antioxidant mimicking the effect of extracellular superoxide dismutase, in preventing instent restenosis in atherosclerotic WHHL-rabbits. The rabbits were given AEOL 10113 (1 mg/kg/d s.c.) or vehicle starting 3 days before stenting of aorta with bare metal stent and continued for 3 or 6 weeks when the animals were sacrificed and the vessels were histologically analysed for morphology, endothelial coverage and inflammation. A specific oxidative stress marker, 8-iso-PGF2α, was measured from plasma to evaluate systemic oxidative stress. AEOL 10113 significantly reduced 8-iso-PGF2α levels from 323±36 to 187±20 pmol/l (p< 0.01) (mean±SEM, n=16) one day after stenting, improved endothelial recovery 3 weeks after stenting by 25.1±9.6 % (p<0.05) as assessed by CD31-immunostaining and decreased restenosis as determined by intima/media ratio (I/M) by 51.3±11.9 % (p<0.01). At 6 weeks, the animals treated with AEOL 10113 showed a 56.3±10.2 % (p<0.001) decrease in I/M and 14.5±5.1% (p<0.05) improvement in endothelial recovery as compared to controls. These findings indicate that AEOL 10113 is able to inhibit neointima formation without interfering with endothelial recovery and is therefore a promising compound to be used for the prevention of instent restenosis.