Antioxidative, antinitrative, and vasculoprotective effects of a peroxisome proliferator-activated receptor-γ agonist in hypercholesterolemia
Antioxidative, antinitrative, and vasculoprotective effects of a peroxisome proliferator-activated receptor-γ agonist in hypercholesterolemia
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DOI：
10.1161/01.cir.0000097003.49585.5e
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发表时间：
2003-12-02
期刊：
影响因子：
37.8
通讯作者：
Yue, TL
中科院分区：
文献类型：
--
作者：
Tao, L;Liu, HR;Yue, TL
背景 - 过氧化物酶体增殖物激活受体 (PPAR) 信号通路已被报道可发挥抗炎作用并减弱动脉粥样硬化的形成。然而，其抗炎和抗动脉粥样硬化作用的机制仍然很大程度上未知。本研究测试了 PPARgamma 激动剂可能通过抗氧化和抗硝化作用发挥显着内皮保护作用的假设。方法和结果-雄性新西兰白兔被随机分配接受正常（对照）或高胆固醇饮食，并用媒介物或罗格列酮（PPARgamma 激动剂）3 mg 治疗。千克（-1）。高胆固醇饮食后 3 周开始，d(-1) 持续 5 周。在8周的高胆固醇饮食结束后，处死兔子，并分离出颈动脉。生物活性一氧化氮通过功能（内皮依赖性血管舒张）和生物化学（血管舒张刺激磷蛋白的磷酸化，或 P-VASP）进行测定。测定血管超氧化物产生、PPARγ、gp91(phox)和诱导型一氧化氮合酶(iNOS)表达以及血管ONOO-形成。尽管 iNOS 表达和总 NOx 产生显着增加，但高胆固醇血症导致严重的内皮功能障碍并降低 P-VASP。罗格列酮治疗可增强 PPARγ 表达，改善内皮依赖性血管舒张，保留 P-VASP，抑制 gp91(phox) 和 iNOS 表达，减少超氧化物和总 NOx 产生，并抑制硝基酪氨酸形成。结论 - PPARγ 激动剂罗格列酮在高胆固醇血症兔中发挥显着的血管保护作用，最有可能是通过减弱氧化和硝化应激。 PPARγ 激动剂的内皮保护作用可能会减少血管壁中白细胞的积累，并有助于其抗动脉粥样硬化作用。
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.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 PPARgamma 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, PPARgamma, 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 NOx production. Treatment with rosiglitazone enhanced PPARgamma expression, improved endothelium-dependent vasodilatation, preserved P-VASP, suppressed gp91(phox) 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.