The Protective Effects Of Pioglitazone On Endothelial Function In Rats With Hypercholesterolemia

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 pioglitazone, 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 pioglitazone (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 pioglitazone 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 pioglitazone 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-VASP. 10mmol/L pioglitazone 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 pioglitazone may exert a significant vasoprotective...