Positive correlation between PPARgamma/PGC-1alpha and gamma-GCS in lungs of rats and patients with chronic obstructive pulmonary disease.
Oxidative stress is one of the major pathogenesis of chronic obstructive pulmonary disease (COPD). gamma-Glutamylcysteine synthetase (gamma-GCS) is one of the paramount antioxidant enzymes in COPD. Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a ligand-activated transcription factor, which is activated by specific ligands such as rosiglitazone (RGZ), exerting multiple biological effects. PPARgamma coactivator-1alpha (PGC-1alpha) is a PPARgamma coactivator, which binds to PPARgamma by induction of PPARgamma ligands, co-activating PPARgamma target genes. Growing evidence has suggested that PPARgamma/PGC-1alpha can regulate multiple antioxidant genes. However, the effect of PPARgamma/PGC-1alpha on gamma-GCS during the development of COPD remains unclear. Here, we measured the expression levels of PPARgamma, PGC-1alpha and gamma-GCS, gamma-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 gamma-GCS activity and increase of the expression levels of PPARgamma, PGC-1alpha, and gamma-GCS. Furthermore, compared with controls, expression levels of PPARgamma, PGC-1alpha, and gamma-GCS significantly increased in the lungs of mild COPD patients, and progressively decreased in lungs of patients with moderate and severe COPD. gamma-GCS protein was positively correlated with FEV(1)%. PPARgamma and PGC-1alpha proteins were positively correlated with gamma-GCS activity and mRNA level. In conclusion, gamma-GCS showed compensatory upregulation in the early stage of COPD, which progressively decompensate with increasing COPD severity. The activation of the PPARgamma/PGC-1alpha pathway may protect against COPD progression by upregulating gamma-GCS and relieving oxidative stress.
Li
Jie
J
Department of Respiratory Medicine, Hunan Institute of Gerontology, Hunan Province Geriatric Hospital, Changsha, China.
Dai
Aiguo
A
Hu
Ruicheng
R
Zhu
Liming
L
Tan
Shuangxiang
S
D000368:Aged; D000818:Animals; D015153:Blotting, Western; D005260:Female; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D012906:Smoke; D045162:Thiazolidinediones / Q000494:pharmacology; D014026:Nicotiana / Q000737:chemistry; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D006360:Heat-Shock Proteins; D008070:Lipopolysaccharides; D047495:PPAR gamma; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; D012906:Smoke; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D005721:Glutamate-Cysteine Ligase