The selective peroxisomal proliferator-activated receptor-gamma agonist has an additive effect on plaque regression in combination with simvastatin in experimental atherosclerosis - In vivo study by high-resolution magnetic resonance imaging
The selective peroxisomal proliferator-activated receptor-gamma agonist has an additive effect on plaque regression in combination with simvastatin in experimental atherosclerosis - In vivo study by high-resolution magnetic resonance imaging
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DOI：
10.1016/j.jacc.2003.08.048
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发表时间：
2004-02-04
影响因子：
24
通讯作者：
Badimon, JJ
中科院分区：
文献类型：
--
作者：
Corti, R;Osende, JI;Badimon, JJ
目的在兔实验性动脉粥样硬化模型中，研究选择性PPAR-γ激动剂和辛伐他汀的抗动脉粥样硬化作用。背景：PPAR是一种核转录因子，控制多种细胞功能，具有诱导斑块消退和稳定所需的潜在作用。将兔随机分为正常饲料(NC饲料)、NC饲料(NC+辛伐他汀)、NC+PPAR-γ激动剂、NC+辛伐他汀+PPAR-γ激动剂。结果随机化时各组动物的MRI血管壁面积(8.45+/-0.65 mm(2))相近，组间比较p=NS。在高脂饮食组有显著的进展(15+/-4%，p<；0.01)。在NC组和NC+PPAR-γ激动剂组，进展被取消(分别为-2.5+/-3%和-4.5+/-5%；p=NS)。NC+辛伐他汀组和NC+辛伐他汀+PPAR-γ激动剂组有显著的斑块消退(分别为-12+/-4%[p<；0.05]和-22+/-4%[p<；0.01])。消退与血脂水平无关。所有NC组在治疗结束时都有相似的血脂谱。病理组织学分析显示，NC组大鼠的巨噬细胞含量和基质金属蛋白酶活性降低，血管内皮细胞/胶原含量增加。结论血脂水平的正常化可阻止动脉粥样硬化的进展。辛伐他汀可引起动脉粥样硬化病变的消退，辛伐他汀联合PPAR-γ激动剂对斑块有相加的消退作用。这与斑块成分的结构变化相平行，这可能会增加斑块的稳定性。这些观察结果支持他汀类药物对动脉粥样硬化的有益作用，并显示了将PPAR-γ激动剂与辛伐他汀联合使用具有抗动脉粥样硬化的额外益处。(C)2004年，由美国心脏病学会基金会提供。
OBJECTIVES We sought to investigate the anti-atherogenic effects of a selective peroxisomal proliferator-activated receptor-gamma (PPAR-gamma) agonist and simvastatin, as well as their combination, over time, in a rabbit model of experimental atherosclerosis.BACKGROUND The PPARs are nuclear transcription factors that control a variety of cellular functions, with the potential,effects required to induce plaque regression and stabilization.METHODS Atherosclerosis was induced in rabbits (n = 37) by the combination of double-balloon injury and a nine-month high-cholesterol (HC diet. The rabbits were randomized into a continued HC diet, a normal chow (NC diet, NC plus simvastatin, NC plus PPAR-gamma agonist, and NC plus simvastatin plus PPAR-gamma agonist. All rabbits underwent magnetic resonance imaging (MRI) at randomization and after six months of treatment and were then sacrificed for histopathologic study.RESULTS All groups had a similar vessel wall area by MRI (8.45 +/- 0.65 mm(2), p = NS between groups) at randomization. Significant progression was seen in the HC diet group (15 +/- 4%, p < 0.01). In the NC and NC plus PPAR-gamma agonist groups, progression was abolished (-2.5 +/- 3% and -4.5 +/- 5%, respectively; p = NS). The NC plus simvastatin and NC plus simvastatin plus PPAR-gamma agonist groups had significant plaque regression (-12 +/- 4% [p < 0.05] and -22 +/- 4% [p < 0.01], respectively). Regression was independent of plasma lipid levels. All NC groups had similar lipid profiles at the end of treatment. Histopathologic analysis of the NC groups showed a decreased macrophage content and matrix metalloproteinase activity and an increased smooth muscle cell/collagen content of lesions.CONCLUSIONS Our data indicate that normalization of plasma lipid levels abolishes progression of atherosclerosis. Simvastatin elicits regression of atherosclerotic lesions, and the combination simvastatin plus PPAR-gamma agonist has additive regression effects on plaque. This is paralleled by structural alterations in plaque composition, which may increase plaque stability. These observations support the beneficial effects of statins on atherosclerosis and show additional anti-atherogenic benefits of combining a PPAR-gamma agonist with simvastatin. (C) 2004 by the American College of Cardiology Foundation.