Abstract 15758: Anti-Inflammatory and Anti-Atherogenic Activities of Ncx 6560, a Nitric Oxide (no)-Donating Statin, in Hypercholesterolemic Mice
NCX 6560 (NCX) was previously shown to prevent platelet-dependent thrombosis in vivo in normocholesterolemic mice. Aim of the present study was to evaluate the anti-inflammatory and anti-atherogenic properties of NCX in an animal model of hypercholesterolemia. We assessed the effects of 3 weeks of oral administration of NCX (6,12 and 24 mg/kg) or of equivalent dose atorvastatin (atorva) (5, 10 and 20 mg/kg) on intimal hyperplasia, atherosclerotic lesions and circulating inflammatory markers in LDL-R−/− mice kept for 16 weeks on a high fat diet (HFD); the femoral artery was photochemically injured and, 3 weeks later, histochemical analysis was carried out. HFD enhanced total and LDL cholesterol (from 294±8.5 to 898±41 mg/dl and from 188±12.6 to 732±62 mg/dl, respectively, p<0.01 for both), increased atherosclerosis-related inflammatory biomarkers (IL-6 from 18±1.8 to 27.1±0.8 pg/ml, p<0.05; sICAM from 463±37 to 524±17 ng/ml, p<0.05) and the degree of injury-induced femoral artery intimal hyperplasia (I/M from 1.15±0.02 to 2±0.34, p<0.01). NCX reduced total and LDL cholesterol dose-dependently, similarly to atorva. NCX, unlike atorva, counteracted significantly the increase of IL-6 at all tested doses (p<0.01 vs control). sICAM was reduced similarly by NCX and atorva, with NCX 24 mg/kg being significantly more effective than equivalent dose atorva (319.3±10.6 vs 415.2±7.3 ng/ml, p<0.05). NCX produced a dose-dependent reduction of injury-induced femoral artery intimal hyperplasia (Intima/Media ratio: Controls=2±0.34; NCX: 6 mg/kg=0.86±0.11; atorva 5 mg/kg=1.3±0.07, p<0.05; NCX 12 mg/kg=0.28±0.14 and atorva 10 mg/kg=1.2±0.11, p<0.01; NCX 24 mg/kg=0.3±0.14 and atorva 20 mg/kg=0.29±0.06; p=NS). NCX, but not atorva, elicited a rise of plasma cGMP, a marker of NO-mediated biological activity (p<0.01 vs control and equivalent atorva). These findings indicate that NCX 6560, a NO-donating statin, exerts enhanced anti-atherogenic properties compared to atorva, suggesting a better potential for the treatment of atherothrombotic disorders.
- © 2010 by American Heart Association, Inc.