Deletion of Caveolin-1 Protects against Oxidative Lung Injury <i>via</i> Up-Regulation of Heme Oxygenase-1

Jin, Yang; Kim, Hong Pyo; Chi, Minli; Ifedigbo, Emeka; Ryter, Stefan W.; Choi, Augustine M.K.

doi:10.1165/rcmb.2007-0323oc

Cited by 65 publications

(66 citation statements)

References 51 publications

(95 reference statements)

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“…Our previous studies demonstrated that deletion of cav-1 protected against hyperoxia-induced cell death (22). Previous studies published by others have established that hyperoxia induces cell death via both necrosis and apoptosis (47).…”

Section: Deletion Of Cav-1 Protected Against Hyperoxia-induced Apoptomentioning

confidence: 84%

“…Our group has previously shown that deletion of cav-1 protects against ALI. Deletion of cav-1 protected both hyperoxia-induced lung injury in vivo and hyperoxic cell death in vitro (22). The mechanisms of this protective effect remain unexplored.…”

Section: Discussionmentioning

confidence: 99%

“…Caveolin-1 (cav-1), a 22-kDa transmembrane scaffolding protein, serves as the principal structural component of caveolae (2,25,36,39). Recent data indicate that cav-1 mediates ALI via a number of different mechanisms, such as increasing hyperoxic cell death and vascular permeability (16,20,22). It is known that deletion of cav-1 protects hyperoxia-induced cell death and ALI both in vitro and in vivo (22); however, the mechanisms remain unclear.…”

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confidence: 99%

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Deletion of caveolin-1 protects hyperoxia-induced apoptosis via survivin-mediated pathways

Zhang

Lin

Lee

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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Cell death is a prominent feature in lungs following prolonged hyperoxia. Caveolae are omega-shaped invaginations of the plasma membrane. Caveolin-1 (cav-1), a 22-kDa transmembrane scaffolding protein, is the principal structural component of caveolae. We have recently shown that deletion of cav-1 (cav-1 Ϫ/Ϫ ) protected against hyperoxia-induced cell death and lung injury both in vitro and in vivo; however, the mechanisms remain unclear. Survivin, a member of the inhibitor of apoptosis protein family, inhibits apoptosis in tumor cells. Although emerging evidence suggests that survivin is involved in wound healing, especially in vascular injuries, its role in hyperoxia-induced lung injury has not been investigated. Our current data demonstrated that hyperoxia induced apoptosis via suppressing survivin expression. Deletion of cav-1 abolished this suppression and subsequently protected against hyperoxia-induced apoptosis. Using "gain" and "loss" of function assays, we determined that survivin protected lung cells from hyperoxia-induced apoptosis via the inhibition of apoptosis executor caspase-3. Overexpression of survivin by deletion of cav-1 was regulated by Egr-1. Egr-1 functioned as a negative regulator of survivin expression. Deletion of cav-1 upregulated survivin via decreased Egr-1 binding of the survivin promoter region. Together, this study illustrates the effect of hyperoxia on survivin expression and the role of survivin in hyperoxia-induced apoptosis. We also demonstrate that deletion of cav-1 protects hyperoxia-induced apoptosis via modulation of survivin expression.caspase-3; Egr-1 ACUTE LUNG INJURY (ALI) and its more severe manifestation, acute respiratory distress syndrome (ARDS), are devastating conditions that account for high morbidity and mortality among critically ill patients (28, 44). Exposure to high O 2 tension (hyperoxia) has been shown in animal models to induce lung injury that closely resembles ARDS. Hyperoxia triggers an extensive inflammatory response in the lung that is typically followed by severe damage of the alveolar-capillary barrier. This damage results in impaired gas exchange and pulmonary edema (10,30,47). Cell death of pulmonary capillary endothelial cells and alveolar epithelial cells is the major pathological change in hyperoxia-injured lungs (1,13,14,26). Compromised epithelial and endothelial cell function leads to fluid and macromolecule accumulation in the air space and can cause clinical respiratory failure and death (1,13,14,26,47).Address for reprint requests and other correspondence: Y. Jin, Division of Pulmonary, Allergy, and Critical Care Medicine, Dept. of Medicine, Univ. of Pittsburgh, MUH 628NW, 3459 5th Ave., Pittsburgh, PA 15213 (e-mail: jiny@upmc.edu). Fig. 1. Deletion of caveolin-1 (cav-1) protected hyperoxia-induced apoptosis. Cells were treated with hyperoxia (time course), and caspase-3 activity was measured as described in MATERIALS AND METHODS. A: wild-type and cav-1 Ϫ/Ϫ fibroblasts were exposed to hyperoxia. Caspase-3 activity was measured. A time c...

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Section: Deletion Of Cav-1 Protected Against Hyperoxia-induced Apoptomentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Deletion of caveolin-1 protects hyperoxia-induced apoptosis via survivin-mediated pathways

Zhang

Lin

Lee

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…The role of Cav-1 in pulmonary diseases remains controversial, and can have protective (23)(24)(25) or deleterious (26,27) functions. Furthermore, the role of Cav-1 in COPD pathogenesis remains poorly understood.…”

Section: Resultsmentioning

confidence: 99%

Autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) activates extrinsic apoptosis during cigarette smoke-induced emphysema

Chen

Lam

Jin

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Chronic obstructive pulmonary disease (COPD) is a debilitating disease caused by chronic exposure to cigarette smoke (CS), which involves airway obstruction and alveolar loss (i.e., emphysema). The mechanisms of COPD pathogenesis remain unclear. Our previous studies demonstrated elevated autophagy in human COPD lung, and as a cellular and tissue response to CS exposure in an experimental model of emphysema in vivo. We identified the autophagic protein microtubule-associated protein 1 light chain-3B (LC3B) as a positive regulator of CS-induced lung epithelial cell death. We now extend these initial observations to explore the mechanism by which LC3B mediates CS-induced apoptosis and emphysema development in vivo. Here, we observed that LC3B −/− mice had significantly decreased levels of apoptosis in the lungs after CS exposure, and displayed resistance to CS-induced airspace enlargement, relative to WT littermate mice. We found that LC3B associated with the extrinsic apoptotic factor Fas in lipid rafts in an interaction mediated by caveolin-1 (Cav-1). The siRNA-dependent knockdown of Cav-1 sensitized epithelial cells to CS-induced apoptosis, as evidenced by enhanced death-inducing signaling complex formation and caspase activation. Furthermore, Cav-1 −/− mice exhibited higher levels of autophagy and apoptosis in the lung in response to chronic CS exposure in vivo. In conclusion, we demonstrate a pivotal role for the autophagic protein LC3B in CS-induced apoptosis and emphysema, suggestive of novel therapeutic targets for COPD treatment. This study also introduces a mechanism by which LC3B, through interactions with Cav-1 and Fas, can regulate apoptosis.

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“…37 Moreover, Cav-1 has been demonstrated in lung epithelial cells to directly interact with Nrf2 to suppress its nuclear translocation, thereby diminishing the induction of ARE-linked antioxidant defense genes 38 ; in addition, it can also interact with HO-1, an Nrf2/ARE-regulated antioxidant enzyme, 39 to attenuate its activity as shown in lung fibroblasts. 40 Taken together, the enhanced Cav-1 expression observed in EC exposed to disturbed FSS 36,41 is likely to contribute to enhanced impaired vascular function, oxidative stress and inflammation, not only via the reduction in NO synthesis but also possibly through diminished cytoprotective activities of both Nrf2 and HO-1.…”

Section: Nrf2 a Mechanosensitive Transcription Factor 21mentioning

confidence: 99%

Nrf2 as an Endothelial Mechanosensitive Transcription Factor

2016

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Deletion of Caveolin-1 Protects against Oxidative Lung Injury via Up-Regulation of Heme Oxygenase-1

Cited by 65 publications

References 51 publications

Deletion of caveolin-1 protects hyperoxia-induced apoptosis via survivin-mediated pathways

Deletion of caveolin-1 protects hyperoxia-induced apoptosis via survivin-mediated pathways

Autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) activates extrinsic apoptosis during cigarette smoke-induced emphysema

Nrf2 as an Endothelial Mechanosensitive Transcription Factor

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