| AIM Peroxisome proliferator-activated receptor(PPAR) signaling pathways have been reported to exert anti-inflammatory effects and attenuate atherosclerosis formation.However,the mechanisms responsible for their anti-inflammatory and antiatherosclerotic effects remain largely unknown.This study was designed to examine the effects of diet-induced hypercholesterolemia on the extent of endothelial(EC) dysfunction and elucidated the potential mechanisms involved. Furthermore,the hypothesis that Rosiglitazone,an agonist of peroxisome proliferator-activated receptor(PPAR)γ,may exert significant endothelial protection by improving NO/cGMP/cGK signaling pathway,which is most important pathway in modulating EC function,was tested.METHODS 36 healthy Male Wistar rats were fed with a normal(Control,n=6) or a high cholesterol(HC,n=30) diets for 8 weeks.Four weeks after being fed a high cholesterol diet,30 HC rats were randomized to receive vehicle(n=6) or Rosiglitazone(HC+PIO,n=24,oral gavage 1.5,3,10,20 mg·kg-1·d-1 during the remaining 4 weeks.At the end of 8 weeks,the rats were anesthetized,and the thoracic aorta was isolated.EC function was determined by comparing vasorelaxation to Ach(acetylcholine),an EC-dependent vasodilator,and acidified NaNO2,an EC-independent vasodilator.Bioactive nitric oxide was determined functionally (endothelium-dependent vasodilatation) and biochemically(the phosphorylation of vasodilator-stimulated phosphoprotein,or p-VASP).The expression of p-VASP in vascular tissue was detected by Western-blot.The level of TCh,TG,HDL-C in the serum was respectively determined by Cholesterol Kit,Triglycerides Kit,and HDL-Cholesterol Kit.The direct effect of Rosiglitazone on vascular tissue was determined by incubating with the thoracic aorta rings in vitro.RESULTS Compared with rats fed with a normal diet,HC rats had increased level of TCh and TG obviously.Hypercholesterolemia caused a significant EC dysfunction(maximal relaxation to Ach:50.51±2.45%vs.99.78%±3.01%in C,P＜0.01) and reduced p-VASP.Treatment with Rosiglitazone attenuated the high level of plasma lipid profiles in diet-induced hypercholesterolemic rats,improved endothelium-dependent vasodilatation in a dose-dependent manner,and preserved p-VASE 10mmol/L Rosiglitazone produced a profound relaxation on the precontraction induced by 1μmol/L PE in the thoracic aorta rings isolated from HC rats;the relaxation was not affected by 0.1mmol/L L-NAME.CONCLUSION Our results demonstrated that HC exacerbate EC function likely by impairing the NO/cGMP/cGK signaling pathway,which is most important pathway in modulating EC function.In addition,our results suggest that Rosiglitazone may exert a significant vasoprotective effect in hypercholesterolemia rats by depressing the level of serum lipid profiles and improving NO bioavailability.Rosiglitazone exert a relaxation on contracted HC rat thoracic aorta,and NO synthesis is not involved in its relaxation. |
