Takata Yasunori, Liu Joey, Yin Fen, Collins Alan R, Lyon Christopher J, Lee Chih-Hao, Atkins Annette R, Downes Michael, Barish Grant D, Evans Ronald M, Hsueh Willa A, Tangirala Rajendra K
Division of Endocrinology, Diabetes, and Hypertension, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-7073, USA.
Proc Natl Acad Sci U S A. 2008 Mar 18;105(11):4277-82. doi: 10.1073/pnas.0708647105. Epub 2008 Mar 12.
Activation of the nuclear hormone receptor peroxisome proliferator-activated receptor delta (PPARdelta) has been shown to improve insulin resistance, adiposity, and plasma HDL levels. However, its antiatherogenic role remains controversial. Here we report atheroprotective effects of PPARdelta activation in a model of angiotensin II (AngII)-accelerated atherosclerosis, characterized by increased vascular inflammation related to repression of an antiinflammatory corepressor, B cell lymphoma-6 (Bcl-6), and the regulators of G protein-coupled signaling (RGS) proteins RGS4 and RGS5. In this model, administration of the PPARdelta agonist GW0742 (1 or 10 mg/kg) substantially attenuated AngII-accelerated atherosclerosis without altering blood pressure and increased vascular expression of Bcl-6, RGS4, and RGS5, which was associated with suppression of inflammatory and atherogenic gene expression in the artery. In vitro studies demonstrated similar changes in AngII-treated macrophages: PPARdelta activation increased both total and free Bcl-6 levels and inhibited AngII activation of MAP kinases, p38, and ERK1/2. These studies uncover crucial proinflammatory mechanisms of AngII and highlight actions of PPARdelta activation to inhibit AngII signaling, which is atheroprotective.
核激素受体过氧化物酶体增殖物激活受体δ（PPARδ）的激活已被证明可改善胰岛素抵抗、肥胖和血浆高密度脂蛋白水平。然而，其抗动脉粥样硬化作用仍存在争议。在此，我们报告了PPARδ激活在血管紧张素II（AngII）加速动脉粥样硬化模型中的抗动脉粥样硬化作用，其特征为与抗炎共抑制因子B细胞淋巴瘤-6（Bcl-6）以及G蛋白偶联信号（RGS）蛋白RGS4和RGS5的抑制相关的血管炎症增加。在该模型中，给予PPARδ激动剂GW0742（1或10 mg/kg）可显著减轻AngII加速的动脉粥样硬化，而不改变血压，并增加动脉中Bcl-6、RGS4和RGS5的血管表达，这与动脉中炎症和动脉粥样硬化相关基因表达的抑制有关。体外研究表明，AngII处理的巨噬细胞也有类似变化：PPARδ激活增加了总Bcl-6水平和游离Bcl-6水平，并抑制了AngII对丝裂原活化蛋白激酶p38和细胞外信号调节激酶1/2的激活。这些研究揭示了AngII的关键促炎机制，并突出了PPARδ激活抑制AngII信号传导的作用，这具有抗动脉粥样硬化保护作用。
