Mitochondrial aldehyde dehydrogenase attenuates hyperoxia-induced cell death through activation of ERK/MAPK and PI3K-Akt pathways in lung epithelial cells

Abstract

Oxygen toxicity is one of the major risk factors in the development of the chronic lung disease or bronchopulmonary dysplasia in premature infants. Using proteomic analysis, we discovered that mitochondrial aldehyde dehydrogenase (mtALDH or ALDH2) was downregulated in neonatal rat lung after hyperoxic exposure. To study the role of mtALDH in hyperoxic lung injury, we overexpressed mtALDH in human lung epithelial cells (A549) and found that mtALDH significantly reduced hyperoxia-induced cell death. Compared with control cells (Neo-A549), the necrotic cell death in mtALDH-overexpressing cells (mtALDH-A549) decreased from 25.3 to 6.5%, 50.5 to 9.1%, and 52.4 to 15.1% after 24-, 48-, and 72-h hyperoxic exposure, respectively. The levels of intracellular and mitochondria-derived reactive oxygen species (ROS) in mtALDH-A549 cells after hyperoxic exposure were significantly lowered compared with Neo-A549 cells. mtALDH overexpression significantly stimulated extracellular signal-regulated kinase (ERK) phosphorylation under normoxic and hyperoxic conditions. Inhibition of ERK phosphorylation partially eliminated the protective effect of mtALDH in hyperoxia-induced cell death, suggesting ERK activation by mtALDH conferred cellular resistance to hyperoxia. mtALDH overexpression augmented Akt phosphorylation and maintained the total Akt level in mtALDH-A549 cells under normoxic and hyperoxic conditions. Inhibition of phosphatidylinositol 3-kinase (PI3K) activation by LY294002 in mtALDH-A549 cells significantly increased necrotic cell death after hyperoxic exposure, indicating that PI3K-Akt activation by mtALDH played an important role in cell survival after hyperoxia. Taken together, these data demonstrate that mtALDH overexpression attenuates hyperoxia-induced cell death in lung epithelial cells through reduction of ROS, activation of ERK/MAPK, and PI3K-Akt cell survival signaling pathways.

Alterations in the diabetic myocardial proteome coupled with increased myocardial oxidative stress underlies diabetic cardiomyopathy

“…However, it has been reported that MST can both oxidize thioredoxin, a key intermediate in cellular redox reactions, and react with peroxides and that this may be a physiologically significant mechanism for combating oxidative challenges [41,42]. Recently, it has been reported that overexpression of ALDH-2 confers lung epithelial cell resistance to hyperoxia-induced cell death in part by reducing intracellular and mitochondrialderived ROS production [43]. Another mechanism by which ALDH-2 may function as an antioxidant involves lipid peroxidation-derived aldehydes (LP-DA).…”

Hyperoxia-induced signal transduction pathways in pulmonary epithelial cells☆

“…Thus, Buckly et al concluded that the ERK-dependent pathway mediates its effects by protecting the basement membrane against hyperoxic DNA strand breakage and death of type II alveolar epithelial cells [52]. A recent study also demonstrates that activation of ERK1/2 induced by either exposure to hyperoxia or over-expression of mitochondrial aldehyde dehydrogenase (mtALDH) attenuates hyperoxia-induced non-apoptotic death of lung epithelial cells through compensatory AKT cell survival signaling pathways [53]. Inosine, a naturally occurring purine with anti-inflammatory properties, was shown to reduce hyperoxicinduced cell death of alveolar epithelium by increasing ERK1/2 activation [54].…”

Over-expression of aldehyde dehydrogenase-2 protects against H2O2-induced oxidative damage and apoptosis in peripheral blood mononuclear cells

“…Several reports have suggested that polymorphism ALDH2 genes have a fundamental relationship with colorectal cancer, primary hepatocellular carcinoma, and stomach cancer [28][29][30][31] . More important, mitochondrial ALDH2 functions as a protector against oxidative stress [14,32,33] . Our subsequent research verified this viewpoint.…”

“…However, further studies are still needed to shed light on these relation ships [14,38] . In summary, this study provides evidence that overexpression of ALDH2 can protect PBMCs against H 2 O 2 -induced oxidative damage and attenuate apoptosis.…”

“…Excessive ROS attacks polyunsaturated fatty acids leading to membrane lipid peroxidation, thereby generating reactive aldehydes, including 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde. ALDH2 provides protection against oxidative damage through the oxidation of exogenous and endogenous aldehydes including 4-HNE, which is the product of lipid peroxidation [13][14][15] . Thus, ALDH2 gene modification may enhance the anti-oxidative stress capacity of immune cells.…”