Department of Physiology and Pharmacology and Health Ageing Research Center, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan.
Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, Xinzhuang, New Taipei City, Taiwan.
Biochem Pharmacol. 2018 Feb;148:222-237. doi: 10.1016/j.bcp.2017.12.024. Epub 2018 Jan 5.
HO-1 (heme oxygenase-1), an antioxidant enzyme, induced by rosiglitazone (PPAR ligands) can be a potential treatment of inflammation. However, the mechanisms of rosiglitazone-induced HO-1 expression in human pulmonary alveolar epithelial cells (HPAEpiCs) remain largely unknown. In this study, we found that upregulation of HO-1 in vitro or in vivo by rosiglitazone attenuated VCAM-1 gene expression and monocyte adhesion to HPAEpiCs challenged with lipopolysaccharide (LPS). The inhibitory effects of rosiglitazone on LPS-mediated responses were reversed by transfection with HO-1 siRNA. LPS-induced VCAM-1 expression was mediated through NF-κB activation which was attenuated by rosiglitazone via suppressing p65 activation and translocation into the nucleus. Moreover, pretreatment with the inhibitor of PKCs (H7), PKCα (Gö6976), AMPKα (Compound C), p38 MAPKα (p38i VIII), SIRT1 (Sirtinol), or PPARγ (T0070907) and transfection with siRNA of PKCα, AMPKα, p38 MAPKα, SIRT1, or PPARγ abolished the rosiglitazone-induced HO-1 expression in HPAEpiCs. Further studies indicated that rosiglitazone stimulated SIRT1 deacetylase leading to PGC1α translocation from the cytosol into the nucleus, promoting fragmentation of NCoR and phosphorylation of PPARγ. Subsequently, PPARγ was activated by phosphorylation of PKCα, AMPKα, p38 MAPKα, and SIRT1, which turned on transcription of HO-1 gene by binding to PPAR response element (PPRE) and enhancing PPARγ promoter activity. These results suggested that rosiglitazone-induced HO-1 expression is mediated through PKCα/AMPKα/p38 MAPKα/SIRT1-dependent deacetylation of Ac-PGC1α and fragmentation of NCoR/PPARγ activation in HPAEpiCs. Up-regulation of HO-1 protected against the inflammatory responses triggered by LPS, at least in part, through attenuation of NF-κB.
HO-1（血红素加氧酶-1）是一种抗氧化酶，可被罗格列酮（PPAR 配体）诱导，可能是炎症的潜在治疗方法。然而，罗格列酮诱导人肺泡上皮细胞（HPAEpiC）中 HO-1 表达的机制在很大程度上仍然未知。在这项研究中，我们发现罗格列酮在体外或体内上调 HO-1 可减弱脂多糖（LPS）刺激的 HPAEpiC 中 VCAM-1 基因表达和单核细胞黏附。用 HO-1 siRNA 转染可逆转罗格列酮对 LPS 介导反应的抑制作用。LPS 诱导的 VCAM-1 表达是通过 NF-κB 激活介导的，罗格列酮通过抑制 p65 激活和核转位来减弱 NF-κB 激活。此外，PKC（H7）、PKCα（Gö6976）、AMPKα（Compound C）、p38 MAPKα（p38i VIII）、SIRT1（Sirtinol）或 PPARγ（T0070907）抑制剂预处理和 PKCα、AMPKα、p38 MAPKα、SIRT1 或 PPARγ 的 siRNA 转染可消除罗格列酮诱导的 HPAEpiC 中 HO-1 的表达。进一步的研究表明，罗格列酮刺激 SIRT1 去乙酰化酶导致 PGC1α 从细胞质易位到核内，促进 NCoR 的片段化和 PPARγ 的磷酸化。随后，PKCα、AMPKα、p38 MAPKα 和 SIRT1 通过磷酸化激活 PPARγ，通过结合 PPAR 反应元件（PPRE）和增强 PPARγ 启动子活性，从而开启 HO-1 基因的转录。这些结果表明，罗格列酮诱导的 HO-1 表达是通过 PKCα/AMPKα/p38 MAPKα/SIRT1 依赖性 Ac-PGC1α 去乙酰化和 NCoR/PPARγ 激活的片段化来介导的。HO-1 的上调可防止 LPS 触发的炎症反应，至少部分是通过抑制 NF-κB 来实现的。
