Reduction of atherosclerosis by the peroxisome proliferator-activated receptor α agonist fenofibrate in mice
Reduction of atherosclerosis by the peroxisome proliferator-activated receptor α agonist fenofibrate in mice
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DOI：
10.1074/jbc.m206966200
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发表时间：
2002-12-13
影响因子：
4.8
通讯作者：
Staels, B
中科院分区：
文献类型：
--
作者：
Duez, H;Chao, YS;Staels, B
几项临床和血管造影干预试验表明，贝特类药物治疗可减少与动脉粥样硬化相关的冠状动脉事件。贝特类药物是过氧化物酶体增殖物激活受体α（PPARalpha）的配体，通过在全身和血管水平发挥作用来调节与动脉粥样硬化相关的危险因素。在此，我们研究了PPARalpha激动剂非诺贝特（FF）治疗对西方饮食喂养的载脂蛋白（apo）E缺陷小鼠和人apoA-I转基因apoE缺陷（hapoA-I Tg x apoE缺陷）小鼠动脉粥样硬化病变发展的影响。在apoE缺陷型小鼠中，FF治疗使血浆脂质水平升高，但胆固醇分布特征无改变。FF治疗没有减少5月龄apoE缺陷小鼠主动脉窦中动脉粥样硬化病变表面积。相比之下，FF治疗降低了这些小鼠降胆固醇中的总胆固醇和酯化胆固醇含量，这种作用在表现出更晚期病变的老年小鼠中更为明显。此外，FF治疗降低MCP-1 mRNA水平在降支动脉的apoE缺陷小鼠，而ABCA-1的表达水平保持尽管主动脉胆固醇含量显着降低。在表达人apoA-I转基因的apoE缺陷小鼠中，FF增加人apoA-I血浆和肝脏mRNA水平，而不影响血浆脂质水平。人apoA-I表达的增加伴随着主动脉窦病变表面积的显着减少。这些数据表明，PPARalpha激动剂非诺贝特在这些动脉粥样硬化动物模型中减少动脉粥样硬化。
Several clinical and angiographic intervention trials have shown that fibrate treatment leads to a reduction of the coronary events associated to atherosclerosis. Fibrates are ligands for peroxisome proliferator-activated receptor a (PPARalpha) that modulate risk factors related to atherosclerosis by acting at both systemic and vascular levels. Here, we investigated the effect of treatment with the PPARalpha agonist fenofibrate (FF) on the development of atherosclerotic lesions in apolipoprotein (apo) E-deficient mice and human apoA-I transgenic apoE-deficient (hapoA-I Tg x apoE-deficient) mice fed a Western diet. In apoE-deficient mice, plasma lipid levels were increased by FF treatment with no alteration in the cholesterol distribution profile. FF treatment did not reduce atherosclerotic lesion surface area in the aortic sinus of 5-month-old apoE-deficient mice. By contrast, FF treatment decreased total cholesterol and esterified cholesterol contents in descending aortas of these mice, an effect that was more pronounced in older mice exhibiting more advanced lesions. Furthermore, FF treatment reduced MCP-1 mRNA levels in the descending aortas of apoE-deficient mice, whereas ABCA-1 expression levels were maintained despite a significant reduction of aortic cholesterol content. In apoE-deficient mice expressing a human apoA-I transgene, FF increased human apoA-I plasma and hepatic mRNA levels without affecting plasma lipid levels. This increase in human apoA-I expression was accompanied by a significant reduction in the lesion surface area in the aortic sinus. These data indicate that the PPARalpha agonist fenofibrate reduces atherosclerosis in these animal models of atherosclerosis.