Peroxisome proliferator-activate inhibit development of atherosclerosis in LDL receptor-deficient mice
Peroxisome proliferator-activate inhibit development of atherosclerosis in LDL receptor-deficient mice
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DOI：
10.1172/jci10370
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发表时间：
2000-08-01
影响因子：
15.9
通讯作者：
Glass, CK
中科院分区：
文献类型：
--
作者：
Li, AC;Brown, KK;Glass, CK
过氧化物酶体增殖体激活受体γ (PPAR γ)是一种调节脂肪细胞发育和葡萄糖稳态的核受体，是一类用于治疗2型糖尿病的胰岛素增敏剂的分子靶点。PPAR γ在动脉粥样硬化病变的巨噬细胞泡沫细胞中高度表达，并在培养的巨噬细胞中被证明可以积极和消极地调节与动脉粥样硬化发展相关的基因。我们在这里报道了PPAR γ特异性激动剂罗格列酮和GW7845强烈抑制LDL受体缺乏的雄性小鼠动脉粥样硬化的发展，尽管动脉壁中CD36清道夫受体的表达增加。雄性小鼠的抗动脉粥样硬化作用与改善胰岛素敏感性和降低组织中tnf - α和明胶酶B的表达有关，表明PPAR γ具有全身和局部作用。这些发现表明PPAR γ激动剂可能在糖尿病患者中发挥抗动脉粥样硬化作用，并为PPAR γ配体的开发提供了动力，该配体可以将促动脉粥样硬化活性与抗糖尿病和抗动脉粥样硬化活性分开。
The peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor that regulates fat-cell development and glucose homeostasis and is the molecular target of a class of insulin-sensitizing agents used for the management of type 2 diabetes mellitus. PPAR gamma is highly expressed in macrophage foam cells of atherosclerotic lesions and has been demonstrated in cultured macrophages to both positively and negatively regulate genes implicated in the development of atherosclerosis. We report here that the PPAR gamma-specific agonists rosiglitazone and GW7845 strongly inhibited the development of atherosclerosis in LDL receptor-deficient male mice, despite increased expression of the CD36 scavenger receptor in the arterial wall. The antiatherogenic effect in male mice was correlated with improved insulin sensitivity and decreased tissue expression of TNF-alpha and gelatinase B, indicating both systemic and local actions of PPAR gamma. These findings suggest that PPAR gamma agonists may exert antiatherogenic effects in diabetic patients and provide impetus for efforts to develop PPAR gamma Ligands that separate proatherogenic activities from antidiabetic and antiatherogenic activities.