Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice.
Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice.
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发表时间：
2000
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通讯作者：
A. Li;K. Brown;M. Silvestre;T. Willson;W. Palinski;C. Glass
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作者：
A. Li;K. Brown;M. Silvestre;T. Willson;W. Palinski;C. Glass
过氧化物酶体增殖物激活受体γ（PPARgamma）是调节脂肪细胞发育和葡萄糖稳态的核受体，并且是用于管理2型糖尿病的一类胰岛素增敏剂的分子靶标。PPARgamma在动脉粥样硬化病变的巨噬细胞泡沫细胞中高度表达，并且已经在培养的巨噬细胞中证明其对动脉粥样硬化发展中涉及的基因进行正性和负性调节。我们在这里报告说，PPARgamma特异性激动剂罗格列酮和GW 7845强烈抑制LDL受体缺陷的雄性小鼠动脉粥样硬化的发展，尽管在动脉壁中的CD 36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胰岛素敏感性改善和TNF-α和明胶酶B的组织表达降低相关，表明PPAR γ的全身和局部作用。这些发现表明，PPARgamma激动剂可能在糖尿病患者中发挥抗动脉粥样硬化作用，并为开发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的PPARgamma配体的努力提供动力。
The peroxisome proliferator-activated receptor gamma (PPARgamma) 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. PPARgamma 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 PPARgamma-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 PPARgamma. These findings suggest that PPARgamma agonists may exert antiatherogenic effects in diabetic patients and provide impetus for efforts to develop PPARgamma ligands that separate proatherogenic activities from antidiabetic and antiatherogenic activities.