Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20814, USA.
Arterioscler Thromb Vasc Biol. 2012 Jan;32(1):65-73. doi: 10.1161/ATVBAHA.111.239137. Epub 2011 Oct 20.
Peroxisome proliferator-activated receptor γ (PPARγ) is widely expressed in vessel walls, and it's activation by agonists showed beneficial effects in cardiovascular diseases. However, the role of endothelial cell (EC) PPARγ in atherogenesis is not fully understood.
To assess the contribution of endothelial-specific PPARγ in atherosclerosis, EC-specific PPARγ disruption and LDL receptor (LDLR) double-knockout (PPARγ(ΔEC)/LDLR(-/-)) mice were developed. When challenged with a high-cholesterol diet for 4 weeks, PPARγ(ΔEC)/LDLR(-/-) mice exhibited severe atherosclerotic lesions compared to either their littermate controls or macrophage-specific PPARγ disruption and LDLR double knockout (PPARγ(ΔMΦ)/LDLR(-/-)) mice. Metabolic analysis showed severe dyslipidemia and significant increase in systolic blood pressure in the PPARγ(ΔEC)/LDLR(-/-) mice. Histological analysis and real-time quantitative PCR suggested an exacerbated inflammation in PPARγ(ΔEC)/LDLR(-/-) mice, as revealed by the increases of proinflammatory gene expression and macrophage infiltration in vivo and in vitro. Furthermore, in vivo endothelial permeability was also increased by endothelial PPARγ disruption. Bone-marrow transplantation studies, which reconstituted hematopoietic PPARγ, demonstrated that the accelerated atherogenesis was due to endothelial PPARγ deficiency.
Endothelial PPARγ plays an important protective role in atherogenesis.
过氧化物酶体增殖物激活受体γ（PPARγ）在血管壁中广泛表达，其激动剂的激活对心血管疾病具有有益作用。然而，内皮细胞（EC）PPARγ 在动脉粥样硬化形成中的作用尚未完全阐明。
为了评估内皮细胞特异性 PPARγ 在动脉粥样硬化形成中的作用，构建了内皮细胞特异性 PPARγ 缺失和 LDL 受体（LDLR）双敲除（PPARγ（ΔEC）/LDLR（-/-））小鼠。当用高胆固醇饮食喂养 4 周时，与同窝对照或巨噬细胞特异性 PPARγ 缺失和 LDLR 双敲除（PPARγ（ΔMΦ）/LDLR（-/-））小鼠相比，PPARγ（ΔEC）/LDLR（-/-）小鼠表现出严重的动脉粥样硬化病变。代谢分析显示，PPARγ（ΔEC）/LDLR（-/-）小鼠存在严重的血脂异常和收缩压显著升高。组织学分析和实时定量 PCR 表明，PPARγ（ΔEC）/LDLR（-/-）小鼠的炎症反应加剧，体内和体外的促炎基因表达和巨噬细胞浸润增加。此外，内皮细胞 PPARγ 缺失也增加了内皮通透性。骨髓移植研究表明，造血细胞中 PPARγ 的重建表明，加速的动脉粥样硬化是由于内皮细胞 PPARγ 缺乏所致。
内皮细胞 PPARγ 在动脉粥样硬化形成中发挥重要的保护作用。
