Abstract
Bcl-2-associated athanogene 1 (Bag-1) is a multifunctional and antiapoptotic protein that binds to the antiapoptosis regulator Bcl-2 and promotes cell survival. To investigate the protective function of Bag-1, we examined the effects of Bag-1L, one isoform of Bag-1, in an in vitro cell culture model of lung ischemia-reperfusion injury (LIRI) generated by treatment of A549 cells with hypoxia/reoxygenation. Overexpression of full-length Bag-1L increased the viability of A549 cells and reduced cell apoptosis in response to 6 h of hypoxia/reoxygenation treatment. Furthermore, Bag-1L overexpression enhanced the heat shock protein 70 (HSP70) and Bcl-2 protein levels, increased the phosphorylation of AKT, decreased Bax and cleaved caspase-3 levels, and was able to overcome cell cycle arrest. These effects were not observed in A549 cells overexpressing a truncated form of Bag-1L lacking the “Bag domain,” denoted Bag-1L△C. The “Bag domain” is the C-terminal 47 amino acids. Taken together, the results of this study suggest that Bag-1L overexpression can protect against oxidative stress and apoptosis in an in vitro LIRI model, with a dependence on the Bag domain.
Highlights
Lung ischemia-reperfusion injury (LIRI) can occur in many clinical conditions such as resuscitation from circulatory arrest, lung transplantation, and trauma [1, 2]
After exposure to hypoxia-reoxygenation for different times, the highest viability of A549 cells was observed after 6 h of treatment, and hypoxia for 6 h was chosen for our further research
Treatment with ly294002, a synthetic phosphoinositide 3-kinase (PI3K) inhibitor, significantly reduced the levels of phosphorylated AKT as well as cell proliferation in the Bag-1L group. These results suggest that Bag-1L may inhibit the cell apoptosis induced by LIRI via PI3K/Akt activation
Summary
Lung ischemia-reperfusion injury (LIRI) can occur in many clinical conditions such as resuscitation from circulatory arrest, lung transplantation, and trauma [1, 2]. Bag-1S is preferentially localized in the cytoplasm [9, 10], but cellular stress causes relocation of cytoplasmic Bag-1S to the nucleus. Both BAG-1S and Bag-1L suppress heat shockinduced apoptosis to the same extent, suggesting a critical role for these isoforms in the nucleus [11]. The Bag domain binds and regulates the heat shock protein 70 (HSP70)/heat shock cognate 70 (HSC70) molecular chaperones, and this activity is closely related to its antiapoptotic function [12]. HSP70 has been shown to effectively protect alveolar epithelial cells against apoptosis and ameliorate the injury caused by LIRI [13]. It is speculated that Bag1/HSP70 interaction may regulate the antiapoptosis effect of Bag-1 in LIRI through the Bag domain
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