Cao Heng, Wen Gao, Li Hongli
Department of Cardiology, Shanghai First People's Hospital, College of Medicine, Shanghai Jiaotong University, Shanghai 200080, P.R. China.
Mol Med Rep. 2014 May;9(5):1755-60. doi: 10.3892/mmr.2014.2020. Epub 2014 Mar 6.
Atherosclerosis is an inflammatory disease involving the immune response. In addition to lowering the cholesterol level, the peroxisome proliferator-activated receptor α (PPAR-α) can prevent atherosclerosis via its pleiotropic anti-inflammatory effects. However, the role of PPAR-α in modulating inflammatory progression of atherosclerosis has rarely been studied. Thus, we aimed to investigate the role of PPAR-α in atherosclerosis by evaluating the expression of inflammatory cytokines induced by PPAR-α in an in vivo rabbit model. New Zealand White rabbits were randomly divided into 5 groups: control, high-fat diet + balloon injury, high-fat diet + balloon injury + placebo, high-fat diet + balloon injury + fenofibrate, and high-fat diet + balloon injury + WY-14643. The femoral arteries of rabbits were balloon-injured after initiation of the high-fat diet and before administration of fenofibrate, WY-14643 or placebo solution. Atherosclerosis was induced by high-fat diet and balloon angioplasty, and the vessel wall lumen occlusion was determined by measuring the stenosis rate. PPAR-α gene expression was examined by quantitative polymerase chain reaction analysis. The cellular localization and distribution of PPAR-α was observed by immunohistochemistry, and its protein level was assessed by western blot analysis. The production of interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α) and P-selectin, which are major inflammatory factors involved in atherosclerosis, was monitored by an enzyme-linked immunosorbent assay (ELISA). Treatment with PPAR-α agonists (fenofibrate or WY-14643) reduced the vascular occlusion rate, as compared to the high-fat diet + balloon injury and the placebo groups. Furthermore, the expression of PPAR-α at both the protein and the mRNA level was increased in the fenofibrate and WY-14643 groups. According to the results, the TNF-α and P-selectin levels were reduced in the fenofibrate and WY-14643 groups. These results suggest that PPAR-α activation can attenuate the effects of atherosclerosis by inhibiting the expression of major inflammatory factors in a rabbit atherosclerosis model.
动脉粥样硬化是一种涉及免疫反应的炎症性疾病。过氧化物酶体增殖物激活受体α（PPAR-α）除了能降低胆固醇水平外，还可通过其多效性抗炎作用预防动脉粥样硬化。然而，PPAR-α在调节动脉粥样硬化炎症进展中的作用鲜有研究。因此，我们旨在通过评估PPAR-α在体内兔模型中诱导的炎症细胞因子表达，来研究PPAR-α在动脉粥样硬化中的作用。将新西兰白兔随机分为5组：对照组、高脂饮食+球囊损伤组、高脂饮食+球囊损伤+安慰剂组、高脂饮食+球囊损伤+非诺贝特组以及高脂饮食+球囊损伤+WY-14643组。在开始高脂饮食后且在给予非诺贝特、WY-14643或安慰剂溶液之前，对兔的股动脉进行球囊损伤。通过高脂饮食和球囊血管成形术诱导动脉粥样硬化，并通过测量狭窄率来确定血管壁管腔闭塞情况。通过定量聚合酶链反应分析检测PPAR-α基因表达。通过免疫组织化学观察PPAR-α的细胞定位和分布，并通过蛋白质印迹分析评估其蛋白水平。通过酶联免疫吸附测定（ELISA）监测白细胞介素-10（IL-10）、肿瘤坏死因子-α（TNF-α）和P-选择素的产生，这些是参与动脉粥样硬化的主要炎症因子。与高脂饮食+球囊损伤组和安慰剂组相比，用PPAR-α激动剂（非诺贝特或WY-14643）治疗可降低血管闭塞率。此外，非诺贝特组和WY-14643组中PPAR-α在蛋白和mRNA水平的表达均增加。根据结果，非诺贝特组和WY-14643组中的TNF-α和P-选择素水平降低。这些结果表明，在兔动脉粥样硬化模型中，激活PPAR-α可通过抑制主要炎症因子的表达来减轻动脉粥样硬化的影响。
