PPARδ-mediated antiinflammatory mechanisms inhibit angiotensin II-accelerated atherosclerosis
PPARδ-mediated antiinflammatory mechanisms inhibit angiotensin II-accelerated atherosclerosis
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DOI：
10.1073/pnas.0708647105
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发表时间：
2008-03-18
影响因子：
11.1
通讯作者：
Tangirala, Rajendra K.
中科院分区：
文献类型：
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作者：
Takata, Yasunori;Liu, Joey;Tangirala, Rajendra K.
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（HDL）水平。然而，其抗动脉粥样硬化作用仍存在争议。在此，我们报道了在血管紧张素II（AngII）加速的动脉粥样硬化模型中PPARδ激活的动脉保护作用，该模型的特征是与抗炎辅阻遏物B细胞淋巴瘤 - 6（Bcl - 6）以及G蛋白偶联信号调节蛋白（RGS）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，且不改变血压，并增加Bcl - 6、RGS4和RGS5的血管表达，这与抑制动脉中炎症和致动脉粥样硬化基因的表达有关。体外研究表明，在AngII处理的巨噬细胞中也有类似变化：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ERK1/2的激活。这些研究揭示了AngII的关键促炎机制，并强调了PPARδ激活抑制AngII信号传导的作用，这具有动脉保护作用。
Activation of the nuclear hormone receptor peroxisome proliferator-activated receptor delta (PPAR delta) has been shown to improve insulin resistance, adiposity, and plasma HDL levels. However, its antiatherogenic role remains controversial. Here we report atheroprotective effects of PPAR delta activation in a model of angiotensin II (AngII)- accelerated atherosclerosis, characterized by increased vascular inf lammation 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 PPAR delta agonist GW0742 (1or 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: PPAR delta 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 PPAR delta activation to inhibit AngII signaling, which is atheroprotective.