PPARδ and PGC1α act cooperatively to induce haem oxygenase-1 and enhance vascular endothelial cell resistance to stress
PPARδ and PGC1α act cooperatively to induce haem oxygenase-1 and enhance vascular endothelial cell resistance to stress
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DOI：
10.1093/cvr/cvp365
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发表时间：
2010-03-01
影响因子：
10.8
通讯作者：
Mason, Justin C.
中科院分区：
文献类型：
--
作者：
Ali, Faisal;Ali, Nadira S.;Mason, Justin C.
过氧化物酶体增殖体激活受体（PPARs）是配体激活转录调节因子核受体超家族的成员。PPAR δ在代谢、伤口愈合和血管生成中有明确的作用。然而，对其在内皮稳态中的作用知之甚少。我们研究了PPAR δ及其共激活剂PPAR γ共激活剂1 α (PGC1 α)通过诱导血红素加氧酶-1在抗氧化损伤血管保护中的作用。小鼠主动脉的面部共聚焦显微镜显示PPAR δ选择性配体GW501516诱导内皮血红素氧化酶-1的表达。体外PPAR δ配体诱导血红素加氧酶-1 mRNA、蛋白和酶活性显著增加，从而增强人内皮细胞对过氧化氢或瘦素诱导的细胞应激的保护作用。此外，腺病毒介导的血红素加氧酶-1的过表达增加了PPAR三角洲启动子活性和mRNA水平，通过正反馈循环放大了PPAR三角洲配体的作用。血红素加氧酶-1启动子/增强子区域的PPAR反应元件结合位点突变表明血红素加氧酶-1是PPAR的直接靶基因。抑制血红素加氧酶-1或PPAR δ均可消除PPAR δ配体诱导的内皮细胞保护作用。此外，PGC1 α的siRNA缺失表明，该共调节因子是PPAR δ配体诱导血红素加氧酶-1及其随后的细胞保护作用的重要PPAR δ转录共激活因子。我们发现了PPAR δ、PGC1 α和血红素加氧酶-1之间的重要关系，表明血红素加氧酶-1的诱导在血管内皮中PPAR δ配体的细胞保护作用中起重要作用。鉴于血红素加氧酶-1对动脉粥样硬化的保护作用，我们认为PPAR δ代表了血管系统中潜在的重要治疗靶点。
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of ligand-activated transcriptional regulators. PPAR delta has an established role in metabolism, wound healing, and angiogenesis. However, little is known about its function in endothelial homeostasis. We investigated the role of PPAR delta and its co-activator, PPAR gamma co-activator 1 alpha (PGC1 alpha), in vasculoprotection against oxidant-induced injury via induction of haem oxygenase-1.En face confocal microscopy of murine aortas demonstrated that the PPAR delta-selective ligand GW501516 induced endothelial haem oxygenase-1 expression. In vitro PPAR delta ligands induced a significant increase in haem oxygenase-1 mRNA, protein, and enzyme activity, resulting in enhanced human endothelial cell protection against cellular stress induced by hydrogen peroxide or leptin. Moreover, adenoviral-mediated overexpression of haem oxygenase-1 increased PPAR delta promoter activity and mRNA levels, amplifying the effect of PPAR delta ligands through a positive feedback loop. Mutation of PPAR response element binding sites in the haem oxygenase-1 promoter/enhancer region revealed haem oxygenase-1 to be a direct PPAR delta target gene. Inhibition of either haem oxygenase-1 or PPAR delta abrogated PPAR delta ligand-induced endothelial cytoprotection. Furthermore, siRNA depletion of PGC1 alpha demonstrated that this co-regulator acts as an essential PPAR delta transcriptional co-activator for haem oxygenase-1 induction by PPAR delta ligands and its subsequent cytoprotective actions.We have identified an important relationship between PPAR delta, PGC1 alpha, and haem oxygenase-1, demonstrating that haem oxygenase-1 induction plays an important role in cytoprotective actions of PPAR delta ligands in vascular endothelium. In light of the protective effects of haem oxygenase-1 against atherogenesis, we suggest that PPAR delta represents a potentially important therapeutic target in the vasculature.