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Role of GPx3 in PPAR?-induced protection against COPD-associated oxidative stress.

ABSTRACT: Cigarette smoke, a source of numerous oxidants, produces oxidative stress and exaggerated inflammatory responses that lead to irreversible lung tissue damage. It is the single, most significant risk factor for chronic obstructive pulmonary disease (COPD). Although an intrinsic defense system that includes both enzymatic and non-enzymatic modulators exists to protect lung tissues against oxidative stress, impairment of these protective mechanisms has been demonstrated in smokers and COPD patients. The antioxidant enzyme GSH peroxidase (GPx) is an important part of this intrinsic defense system. Although cigarette smoke has been shown to downregulate its expression and activity, the underlying mechanism is not known. Peroxisome proliferator-activated receptor ? (PPAR?) is a nuclear hormone receptor with antioxidant effects. PPAR? activation has demonstrated protective effects against cigarette smoke-induced oxidative stress and inflammation. Molecular mechanisms for PPAR?'s antioxidant function likewise remain to be elucidated. This study explored the link between PPAR? and GPx3 and found a positive association in cigarette smoke extract (CSE)-exposed human bronchial epithelial cells. Moreover, we provide evidence that identifies GPx3 as a PPAR? transcriptional target. Attenuation of antioxidant effects in the absence of GPx3 highlights the antioxidant's prominent role in mediating PPAR?'s function. We also demonstrate that ligand-mediated PPAR? activation blocks CSE-induced reactive oxygen species and hydrogen peroxide production via upregulation of GPx3. In summary, our findings describing the molecular mechanisms involving GPx3 and PPAR? in CSE-induced oxidative stress and inflammation may provide valuable information for the development of more effective therapeutics for COPD.

SUBMITTER: Reddy AT

PROVIDER: S-EPMC6368849 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Role of GPx3 in PPARγ-induced protection against COPD-associated oxidative stress.

Reddy Aravind T AT Lakshmi Sowmya P SP Banno Asoka A Reddy Raju C RC

Free radical biology & medicine 20180815

Cigarette smoke, a source of numerous oxidants, produces oxidative stress and exaggerated inflammatory responses that lead to irreversible lung tissue damage. It is the single, most significant risk factor for chronic obstructive pulmonary disease (COPD). Although an intrinsic defense system that includes both enzymatic and non-enzymatic modulators exists to protect lung tissues against oxidative stress, impairment of these protective mechanisms has been demonstrated in smokers and COPD patients ...[more]

PMID: 30118830

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Project description:In this study, cell death induced by the oxidant tert-butylhydroperoxide (tBH) was observed in U2OS cells; this phenotype was rescued by Syntaxin 17 (STX17) knockout (KO) but the mechanism is unknown. STX17 plays dual roles in autophagosome-lysosome fusion and mitochondrial fission. However, the contribution of the two functions of STX17 to apoptosis has not been extensively studied. Here, we sought to dissect the dual roles of STX17 in oxidative-stress-induced apoptosis by taking advantage of STX17 knockout cells and an autophagosome-lysosome fusion defective mutant of STX17. We generated STX17 knockout U2OS cells using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and the STX17 knockout cells were reconstituted with wild-type STX17 and its autophagosome-lysosome fusion defective mutant. Autophagy was assessed by autophagic flux assay, Monomer red fluorescent protein (mRFP)-GFP-LC3 assay and protease protection assay. Golgi, endoplasmic reticulum (ER)/ER-Golgi intermediate compartment (ERGIC) and mitochondrial dynamics were examined by staining the different indicator proteins. Apoptosis was evaluated by caspase cleavage assay. The general reactive oxygen species (ROS) were detected by flow cytometry. In STX17 complete knockout cells, sealed autophagosomes were efficiently formed but their fusion with lysosomes was less defective. The fusion defect was rescued by wild-type STX17 but not the autophagosome-lysosome fusion defective mutant. No obvious defects in Golgi, ERGIC or ER dynamics were observed. Mitochondria were significantly elongated, supporting a role of STX17 in mitochondria fission and the elongation caused by STX17 KO was reversed by the autophagosome-lysosome fusion defective mutant. The clearance of protein aggregation was compromised, correlating with the autophagy defect but not with mitochondrial dynamics. This study revealed a mixed role of STX17 in autophagy, mitochondrial dynamics and oxidative stress response. STX17 knockout cells were highly resistant to oxidative stress, largely due to the function of STX17 in mitochondrial fission rather than autophagy.

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Role of GPx3 in PPAR?-induced protection against COPD-associated oxidative stress.

Publications

Role of GPx3 in PPARγ-induced protection against COPD-associated oxidative stress.

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