Published Online
on November 10, 2003

A more recent version of this article appeared on December 2, 2003

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Submitted on April 23, 2003
Revised on July 31, 2003
Accepted on August 1, 2003

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

Ling Tao MD, Hui-Rong Liu MD, PhD, Erhe Gao MD, PhD, Zhi-Ping Teng MD, PhD, Bernard L. Lopez MD, Theodore A. Christopher MD, Xin-Liang Ma MD, PhD^*, Ines Batinic-Haberle PhD, Robert N. Willette PhD, Eliot H. Ohlstein PhD, and Tian-Li Yue PhD

From the Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, Pa; the Department of Radiation Oncology, Duke University Medical Center, Durham, NC (I.B.-H.); and GlaxoSmithKline Pharmaceuticals, King of Prussia, Pa (R.N.W., E.H.O., T.-L.Y.).

^* To whom correspondence should be addressed. E-mail: xin.ma{at}jefferson.edu.

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 PPAR 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 PPAR 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, PPAR, gp91^phox, 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 NO_x production. Treatment with rosiglitazone enhanced PPAR expression, improved endothelium-dependent vasodilatation, preserved P-VASP, suppressed gp91^phox and iNOS expression, reduced superoxide and total NO_x production, and inhibited nitrotyrosine formation.

Conclusions--The PPAR 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 PPAR agonists may reduce leukocyte accumulation in vascular walls and contribute to their antiatherosclerotic effect.

Key words: hypercholesterolemia • endothelium • inflammation • atherosclerosis

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