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Acta Biochimica et Biophysica Sinica
Year: 2010  |  Volume: 42  |  Issue: 9  |  Page No.: 603 - 614

Positive correlation between PPAR{gamma}/PGC-1{alpha} and {gamma}-GCS in lungs of rats and patients with chronic obstructive pulmonary disease

J Li, A Dai, R Hu, L Zhu and S. Tan    

Abstract:

Oxidative stress is one of the major pathogenesis of chronic obstructive pulmonary disease (COPD). -Glutamylcysteine synthetase (-GCS) is one of the paramount antioxidant enzymes in COPD. Peroxisome proliferator-activated receptor-gamma (PPAR) is a ligand-activated transcription factor, which is activated by specific ligands such as rosiglitazone (RGZ), exerting multiple biological effects. PPAR coactivator-1 (PGC-1) is a PPAR coactivator, which binds to PPAR by induction of PPAR ligands, co-activating PPAR target genes. Growing evidence has suggested that PPAR/PGC-1 can regulate multiple antioxidant genes. However, the effect of PPAR/PGC-1 on -GCS during the development of COPD remains unclear. Here, we measured the expression levels of PPAR, PGC-1 and -GCS, -GCS activity and reactive oxygen species (ROS) contents in lungs of rats treated by cigarette smoke (CS) + lipopolysaccharide (LPS) and CS + LPS + RGZ, as well as lungs of patients suffered from COPD. Compared with lungs from CS + LPS-treated rats, lungs of RGZ-treated rats demonstrated markedly lower ROS contents, and remarkable increase of -GCS activity and increase of the expression levels of PPAR, PGC-1, and -GCS. Furthermore, compared with controls, expression levels of PPAR, PGC-1, and -GCS significantly increased in the lungs of mild COPD patients, and progressively decreased in lungs of patients with moderate and severe COPD. -GCS protein was positively correlated with FEV1%. PPAR and PGC-1 proteins were positively correlated with -GCS activity and mRNA level. In conclusion, -GCS showed compensatory upregulation in the early stage of COPD, which progressively decompensate with increasing COPD severity. The activation of the PPAR/PGC-1 pathway may protect against COPD progression by upregulating -GCS and relieving oxidative stress.

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