Antioxidative, antinitrative, and vasculoprotective effects of a peroxisome proliferator-activated receptor-gamma agonist in hypercholesterolemia.
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 PPARgamma agonist may exert significant endothelial protection by antioxidative and antinitrative effects.


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 PPARgamma agonist) 3 mg x kg(-1) x 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, PPARgamma, 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 PPARgamma 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 PPARgamma 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 PPARgamma agonists may reduce leukocyte accumulation in vascular walls and contribute to their antiatherosclerotic effect.
Tao
Ling
L
Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, Pa 19107, USA.
Liu
Hui-Rong
HR
Gao
Erhe
E
Teng
Zhi-Ping
ZP
Lopez
Bernard L
BL
Christopher
Theodore A
TA
Ma
Xin-Liang
XL
Batinic-Haberle
Ines
I
Willette
Robert N
RN
Ohlstein
Eliot H
EH
Yue
Tian-Li
TL
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001808:Blood Vessels / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D066298:In Vitro Techniques; D008055:Lipids / Q000097:blood; D008297:Male; D009566:Nitrates / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D011817:Rabbits; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D014157:Transcription Factors / Q000819:agonists*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
D000975:Antioxidants; D008055:Lipids; D009566:Nitrates; D009573:Nitrites; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP