Bywaters Center for Vascular Inflammation, Cardiovascular Sciences, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK.
Cardiovasc Res. 2010 Mar 1;85(4):701-10. doi: 10.1093/cvr/cvp365. Epub 2009 Nov 10.
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of ligand-activated transcriptional regulators. PPARdelta 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 PPARdelta and its co-activator, PPARgamma co-activator 1alpha (PGC1alpha), in vasculoprotection against oxidant-induced injury via induction of haem oxygenase-1.
En face confocal microscopy of murine aortas demonstrated that the PPARdelta-selective ligand GW501516 induced endothelial haem oxygenase-1 expression. In vitro PPARdelta 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 PPARdelta promoter activity and mRNA levels, amplifying the effect of PPARdelta 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 PPARdelta target gene. Inhibition of either haem oxygenase-1 or PPARdelta abrogated PPARdelta ligand-induced endothelial cytoprotection. Furthermore, siRNA depletion of PGC1alpha demonstrated that this co-regulator acts as an essential PPARdelta transcriptional co-activator for haem oxygenase-1 induction by PPARdelta ligands and its subsequent cytoprotective actions.
We have identified an important relationship between PPARdelta, PGC1alpha, and haem oxygenase-1, demonstrating that haem oxygenase-1 induction plays an important role in cytoprotective actions of PPARdelta ligands in vascular endothelium. In light of the protective effects of haem oxygenase-1 against atherogenesis, we suggest that PPARdelta represents a potentially important therapeutic target in the vasculature.
过氧化物酶体增殖物激活受体（PPARs）是配体激活转录调节因子的核受体超家族的成员。PPARδ在代谢、伤口愈合和血管生成中具有明确的作用。然而，其在内皮细胞稳态中的功能知之甚少。我们通过诱导血红素加氧酶-1（HO-1）来研究 PPARδ及其共激活因子 PPARγ共激活因子 1α（PGC1α）在对抗氧化剂诱导的损伤中的血管保护作用。
对鼠主动脉进行共聚焦显微镜检查显示，PPARδ 选择性配体 GW501516 诱导内皮细胞 HO-1 表达。体外 PPARδ 配体显著增加 HO-1 mRNA、蛋白和酶活性，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 HO-1 过表达增加了 PPARδ 启动子活性和 mRNA 水平，通过正反馈环放大了 PPARδ 配体的作用。HO-1 启动子/增强子区域中 PPAR 反应元件结合位点的突变表明 HO-1 是 PPARδ 的直接靶基因。HO-1 或 PPARδ 的抑制消除了 PPARδ 配体诱导的内皮细胞保护作用。此外，PGC1α 的 siRNA 耗竭表明，该共调节剂是 PPARδ 配体诱导 HO-1 及其随后的细胞保护作用的必需 PPARδ 转录共激活因子。
我们已经确定了 PPARδ、PGC1α 和 HO-1 之间的重要关系，表明 HO-1 诱导在 PPARδ 配体在血管内皮细胞中的细胞保护作用中起着重要作用。鉴于 HO-1 对动脉粥样硬化的保护作用，我们认为 PPARδ 是血管系统中一个潜在的重要治疗靶点。
