Objective To explore the regulation of peroxisome proliferator-activated receptor γ coactivator 1α( PGC-1α) and NF-E2-related factor 2( Nrf2) on expression of γ-glutamylcysteine synthetase ( γ-GCS) , and their roles in chronic obstructive pulmonary disease( COPD) . Methods Twenty-four SD rats were randomly divided into a COPD group and a normal control group. COPD model was established by intratracheal instillation of lipopolysaccharide ( LPS) and daily exposure to cigarette smog in the COPD group. The lung function was measured and the pathological changes were observed. The protein and mRNA expressions of PGC-1α, Nrf2, and γ-GCS in lung tissue were measured by immunohistochemistry, Western blot, in site hybridization ( ISH) , and reverse transcription-polymerase chain reaction ( RT-PCR ) ,
respectively. Results In the COPD group, the pulmonary function ( FEV0. 3, FEV0. 3 /FVC, PEF) damage and lung pathological changes were conformed as morphological characteristics of COPD. The mRNA of PGC-1α and Nrf2 expressed in lung tissues of two group rats in the region consistent with γ-GCS mRNA. The protein and mRNA expressions of PGC-1αand γ-GCS were markedly increased in the COPD group( all P lt;0. 05) ,and the protein expression of Nrf2 was obviously up-regulated ( P lt; 0. 01) , while Nrf2 mRNA had no significant difference between the two groups( P gt;0. 05 ) . Linear correlation analysis showed that the level of
PGC-1αprotein was positively correlated with the levels of Nrf2 protein and mRNA ( r = 0. 775, 0. 515, all P lt; 0. 01) , and the levels of PGC-1αand Nrf2 protein were positively correlated with the levels of γ-GCS protein ( r = 0. 531, 0. 575, all P lt; 0. 01) and mRNA ( r = 0. 616, 0. 634, all P lt; 0. 01) . Conclusions PGC-1α, which may serve as a co-activator of Nrf2, can up-regulate the expression of γ-GCS gene cooperatively with Nrf2 through a common pathway, which might involve in the oxidative and antioxidative mechanism in the pathogenesis of COPD.
Citation：
LI Jie,DAI Aiguo,Wang Meifang,HU Ruicheng,ZHU Liming. Roles of PGC-1α and Nrf2 Synergistic Regulating γ-Glutamylcysteine Synthetase in Rats with Chronic Obstructive Pulmonary Disease. Chinese Journal of Respiratory and Critical Care Medicine, 2009, 09(6): 528-533. doi:
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Copyright © the editorial department of Chinese Journal of Respiratory and Critical Care Medicine of West China Medical Publisher. All rights reserved
| 1. |
林书典, 戴爱国, 唐朝克. γ谷氨酰半胱氨酸合成酶在大鼠慢性阻塞性肺疾病中的表达. 中华结核和呼吸杂志, 2004, 27: 348 -349.
|
| 2. |
林书典, 戴爱国, 徐平. 慢性阻塞性肺疾病患者γ谷氨酰半胱氨酸合成酶活性及表达的变化. 中华结核和呼吸杂志, 2005,28: 97-101.
|
| 3. |
陈林, 戴爱国, 胡瑞成. 核因子相关因子2 及其蛋白激酶与γ谷氨酰半胱氨酸合成酶在慢性阻塞性肺疾病大鼠肺组织的表达.中华结核和呼吸杂志, 2006, 29: 487-488.
|
| 4. |
Clark J, Simon DK. Transcribe to Survive: transcriptional control of antioxidant defense programs for neuroprotection in Parkinson ’ s disease. Antioxid Redox Signal, 2009, 11: 509-528.
|
| 5. |
宋一平, 王德良, 茅培英, 等. 慢性阻塞性肺疾病大鼠模型的建立及药物干预的影响. 中华内科杂志, 2000, 39: 556-557.
|
| 6. |
中华医学会呼吸病学分会慢性阻塞性肺疾病学组. 慢性阻塞性肺疾病诊治指南( 2007 年修订版) . 中华结核和呼吸杂志,2007, 30: 8-17.
|
| 7. |
Cortes-Wanstreet MM, Giedzinski E, Limoli CL, et al.Overexpression of glutamate-cysteine ligase protects human COV434 granulosa tumour cells against oxidative and gamma -radiationinduced cell death. Mutagenesis, 2009, 24: 211-224.
|
| 8. |
朱黎明, 曹守冬, 戴爱国. 哮喘患者γ-谷氨酰半胱氨酸合成酶及还原型谷胱甘肽的活性变化. 中国呼吸与危重监护杂志,2008, 7: 459-462.
|
| 9. |
Rangasamy T, Cho CY, Thimmulappa RK, et al. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J Clin Invest, 2004, 114: 1248.
|
| 10. |
Lee JM, Johnson JA. An important role of Nrf2-ARE pathway in the cellular defense mechanism. J Biochem Mol Biol, 2004 , 37: 139 -143.
|
| 11. |
Nguyen T, Yang CS, Pickett CB. The pathways and molecular mechanisms regulating Nrf2 activation in response to chemical stress. Free Radic Biol Med, 2004, 37: 433.
|
| 12. |
Adair-Kirk TL, Atkinson JJ, Griffin GL, et al. Distal airways in mice exposed to cigarette smoke: Nrf2-regulated genes are increased in Clara cells. Am J Respir Cell Mol Biol, 2008, 39: 400-411.
|
| 13. |
St-Pierre J, Drori S, Uldry M, et al. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell, 2006, 127: 397-408.
|
- 1. 林书典, 戴爱国, 唐朝克. γ谷氨酰半胱氨酸合成酶在大鼠慢性阻塞性肺疾病中的表达. 中华结核和呼吸杂志, 2004, 27: 348 -349.
- 2. 林书典, 戴爱国, 徐平. 慢性阻塞性肺疾病患者γ谷氨酰半胱氨酸合成酶活性及表达的变化. 中华结核和呼吸杂志, 2005,28: 97-101.
- 3. 陈林, 戴爱国, 胡瑞成. 核因子相关因子2 及其蛋白激酶与γ谷氨酰半胱氨酸合成酶在慢性阻塞性肺疾病大鼠肺组织的表达.中华结核和呼吸杂志, 2006, 29: 487-488.
- 4. Clark J, Simon DK. Transcribe to Survive: transcriptional control of antioxidant defense programs for neuroprotection in Parkinson ’ s disease. Antioxid Redox Signal, 2009, 11: 509-528.
- 5. 宋一平, 王德良, 茅培英, 等. 慢性阻塞性肺疾病大鼠模型的建立及药物干预的影响. 中华内科杂志, 2000, 39: 556-557.
- 6. 中华医学会呼吸病学分会慢性阻塞性肺疾病学组. 慢性阻塞性肺疾病诊治指南( 2007 年修订版) . 中华结核和呼吸杂志,2007, 30: 8-17.
- 7. Cortes-Wanstreet MM, Giedzinski E, Limoli CL, et al.Overexpression of glutamate-cysteine ligase protects human COV434 granulosa tumour cells against oxidative and gamma -radiationinduced cell death. Mutagenesis, 2009, 24: 211-224.
- 8. 朱黎明, 曹守冬, 戴爱国. 哮喘患者γ-谷氨酰半胱氨酸合成酶及还原型谷胱甘肽的活性变化. 中国呼吸与危重监护杂志,2008, 7: 459-462.
- 9. Rangasamy T, Cho CY, Thimmulappa RK, et al. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J Clin Invest, 2004, 114: 1248.
- 10. Lee JM, Johnson JA. An important role of Nrf2-ARE pathway in the cellular defense mechanism. J Biochem Mol Biol, 2004 , 37: 139 -143.
- 11. Nguyen T, Yang CS, Pickett CB. The pathways and molecular mechanisms regulating Nrf2 activation in response to chemical stress. Free Radic Biol Med, 2004, 37: 433.
- 12. Adair-Kirk TL, Atkinson JJ, Griffin GL, et al. Distal airways in mice exposed to cigarette smoke: Nrf2-regulated genes are increased in Clara cells. Am J Respir Cell Mol Biol, 2008, 39: 400-411.
- 13. St-Pierre J, Drori S, Uldry M, et al. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell, 2006, 127: 397-408.
