Background-The ubiquitin-proteasome system is the major intracellular protein degradation pathway in eucaryotic cells.It regulates central mediators of proliferation, inflammation, and apoptosis that are fundamental pathomechanisms in the development of vascular restenosis. Methods and Results-Effects of proteasome inhibition on neointima formation were studied in a balloon injury model in the rat carotid artery. Local application of the proteasome inhibitor MG132 (1 mmol/L) resulted in significant inhibition of intimal hyperplasia, that is, by 74% (Pϭ0.008). This effect was accompanied by decreased proliferation, reduced infiltration of macrophages, and prolonged apoptosis, as determined by immunohistochemical and TUNEL analyses. Functional effects of proteasome inhibition on proliferation, activation of nuclear factor kappa B, and apoptosis were further characterized in rat primary vascular smooth muscle cells. MG132 dose-dependently inhibited vascular smooth muscle cell proliferation with 50% inhibition at 10 mol/L. TNF␣-induced degradation of IB␣ and ␤ was blocked, and activation of nuclear factor kappa B was suppressed in a concentration-dependent manner in bandshift assays. Moreover, proteasome inhibition (1 to 50 mol/L MG132) induced apoptotic cell death up to 80%, as confirmed by DNA/Histone-ELISA and TUNEL-FACS analysis. Specificity of proteasome inhibition was shown by accumulation of multiubiquitinylated proteins and accumulation of specific proteasomal substrates. Conclusions-These proof-of-principle experiments demonstrate that inhibition of the ubiquitin-proteasome system effectively reduces neointima formation in vivo, which corresponds to strong antiproliferative, anti-inflammatory, and proapoptotic effects in vitro and in vivo. Our data suggest the ubiquitin-proteasome system as a new target in the prevention of vascular restenosis.

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Background and Purpose-To test the feasibility of self-expanding drug-coated nitinol stents for prevention of restenosis in an animal model. Stent implantation in the carotid artery (CA) has been shown to be feasible for treatment of CA stenosis. Even though the restenosis rate in CA is reported to be lower than in the coronary and peripheral arteries, problems may arise with increasing numbers of treated patients and lengthier follow-up. Methods-After predilatation with 8-mm balloons, 8 Goettinger minipigs were randomly selected to receive a sirolimus-eluting self-expanding nitinol stent (7 mm/80 mm) as well as the same stent without sirolimus/polymer coating in the right or left CA. Aspirin was given starting 3 days before the intervention and administered for an additional 4 weeks. Clopidogrel was administered for 10 days. Results-After 6 weeks, 2 subacute occlusions were observed in both groups. In the remaining vessels, the neointima was significantly reduced by sirolimus/polymer-coated stents (5.9Ϯ2.5 versus 0.7Ϯ1.0 mm 2 ). Conclusions-Sirolimus self-expanding nitinol stents may be an effective tool in reducing neointimal formation in CA.(Stroke. 2006;37:492-494.)

NIR-RS might be useful for the determination of contrast media-induced side effects. Stable prostacyclin analogues or phosphodiesterase inhibitors have the potential to mitigate these side effects.