Peroxisome proliferator-activated receptor-γ ligands induce heme oxygenase-1 in lung fibroblasts by a PPARγ-independent, glutathione-dependent mechanism
Peroxisome proliferator-activated receptor-γ ligands induce heme oxygenase-1 in lung fibroblasts by a PPARγ-independent, glutathione-dependent mechanism
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DOI：
10.1152/ajplung.00148.2009
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发表时间：
2009-11-01
影响因子：
4.9
通讯作者：
Sime, Patricia J.
中科院分区：
文献类型：
--
作者：
Ferguson, Heather E.;Thatcher, Thomas H.;Sime, Patricia J.
弗格森，撒切尔，奥尔森，KC，加西亚-贝茨TM，Baglole CJ，Kottmann RM，Strong ER，菲普斯RP，Sime PJ。过氧化物酶体增殖物激活的受体-γ配体通过PPARγ不依赖、谷胱甘肽依赖的机制诱导肺成纤维细胞中的血红素加氧酶-1。Am J Physiol肺细胞分子Physiol 297：L912-L919,2009。-氧化应激在肺纤维化的发病机制中起着重要作用。血红素氧合酶-1(HO-1)是一种关键的抗氧化酶，在动物模型中过表达HO-1可显著减少肺部炎症和纤维化。过氧化物酶体增殖物激活受体-γ(PPAR-Gamma)是一种转录因子，调节脂肪生成、胰岛素增敏和炎症。我们报道了PPARγ配体15d-PGJ(2)和2-氰基-3，12-二氧杂环烯-1，9-二烯-28-酸(CDDO)在体外具有很强的抗纤维化作用，也能强烈诱导原代培养的人肺成纤维细胞表达HO-1。药理学和遗传学方法被用来证明HO-1的诱导是PPAR伽马不依赖的。HO-1的上调与细胞内谷胱甘肽(GSH)水平的降低相一致，并可被硫醇抗氧化剂和GSH前体N-乙酰半胱氨酸(NAC)抑制。HO-1的上调不被非硫醇抗氧化剂Trolox抑制，也不涉及转录因子AP-1或Nrf2。CDDO和15d-PGJ(2)含有一个作为亲电中心的α/β不饱和酮，它可以与自由还原的硫醇形成共价键。罗格列酮是一种PPAR伽马配体，缺乏亲电中心，不能诱导HO-1。这些结果表明，在人肺成纤维细胞中，15d-PGJ(2)和CDDO通过GSH依赖的机制诱导HO-1，15d-PGJ(2)或CDDO与GSH之间形成共价键。NAC抑制HO-1的表达对15d-PGJ(2)和CDDO的体外抗纤维化作用影响不大。这些结果表明，CDDO和类似的亲电PPARγ配体作为抗纤维化药物可能具有巨大的临床潜力，不仅通过直接影响成纤维细胞的分化和功能，而且间接通过增强抗氧化防御。
Ferguson HE, Thatcher TH, Olsen KC, Garcia-Bates TM, Baglole CJ, Kottmann RM, Strong ER, Phipps RP, Sime PJ. Peroxisome proliferator-activated receptor-gamma ligands induce heme oxygenase-1 in lung fibroblasts by a PPAR gamma-independent, glutathione-dependent mechanism. Am J Physiol Lung Cell Mol Physiol 297: L912-L919, 2009. First published September 4, 2009; doi: 10.1152/ajplung.00148.2009.-Oxidative stress plays an important role in the pathogenesis of pulmonary fibrosis. Heme oxygenase-1 (HO-1) is a key antioxidant enzyme, and overexpression of HO-1 significantly decreases lung inflammation and fibrosis in animal models. Peroxisome proliferator-activated receptor-gamma (PPAR gamma) is a transcription factor that regulates adipogenesis, insulin sensitization, and inflammation. We report here that the PPAR gamma ligands 15d-PGJ(2) and 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO), which have potent antifibrotic effects in vitro, also strongly induce HO-1 expression in primary human lung fibroblasts. Pharmacological and genetic approaches are used to demonstrate that induction of HO-1 is PPAR gamma independent. Upregulation of HO-1 coincides with decreased intracellular glutathione (GSH) levels and can be inhibited by N-acetyl cysteine (NAC), a thiol antioxidant and GSH precursor. Upregulation of HO-1 is not inhibited by Trolox, a non-thiol antioxidant, and does not involve the transcription factors AP-1 or Nrf2. CDDO and 15d-PGJ(2) contain an alpha/beta unsaturated ketone that acts as an electrophilic center that can form covalent bonds with free reduced thiols. Rosiglitazone, a PPAR gamma ligand that lacks an electrophilic center, does not induce HO-1. These data suggest that in human lung fibroblasts, 15d-PGJ(2) and CDDO induce HO-1 via a GSH-dependent mechanism involving the formation of covalent bonds between 15d-PGJ(2) or CDDO and GSH. Inhibiting HO-1 upregulation with NAC has only a small effect on the antifibrotic properties of 15d-PGJ(2) and CDDO in vitro. These results suggest that CDDO and similar electrophilic PPAR gamma ligands may have great clinical potential as antifibrotic agents, not only through direct effects on fibroblast differentiation and function, but indirectly by bolstering antioxidant defenses.