Antioxidative, Antinitrative, and Vasculoprotective Effects of a Peroxisome Proliferator–Activated Receptor-γ Agonist in Hypercholesterolemia

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Abstract
Background— 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. The present study tested the hypothesis that a PPARγ agonist may exert significant endothelial protection by antioxidative and antinitrative effects. Methods and Results— Male New Zealand White rabbits were randomized to receive a normal (control) or a high-cholesterol diet and treated with vehicle or rosiglitazone (a PPARγ agonist) 3 mg · kg−1 · d−1 for 5 weeks beginning 3 weeks after the high-cholesterol diet. At the end of 8 weeks of a high-cholesterol diet, the rabbits were killed, and the carotid arteries were isolated. Bioactive nitric oxide was determined functionally (endothelium-dependent vasodilatation) and biochemically (the phosphorylation of vasodilator-stimulated phosphoprotein, or P-VASP). Vascular superoxide production, PPARγ, gp91phox, and inducible nitric oxide synthase (iNOS) expression, and vascular ONOO− formation were determined. Hypercholesterolemia caused severe endothelial dysfunction and reduced P-VASP, despite a marked increase in iNOS expression and total NOx production. Treatment with rosiglitazone enhanced PPARγ expression, improved endothelium-dependent vasodilatation, preserved P-VASP, suppressed gp91phox and iNOS expression, reduced superoxide and total NOx production, and inhibited nitrotyrosine formation. Conclusions— The PPARγ agonist rosiglitazone exerted a significant vascular protective effect in hypercholesterolemic rabbits, most likely by attenuation of oxidative and nitrative stresses. The endothelial protective effects of PPARγ agonists may reduce leukocyte accumulation in vascular walls and contribute to their antiatherosclerotic effect.