Abstract
Acrolein is known to be involved in acute lung injury and other pulmonary diseases. A number of studies have suggested that acrolein-induced toxic effects are associated with depletion of antioxidants and production of reactive oxygen species. Mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2) regulates mitochondrial redox balance and reduces oxidative stress-induced cell injury via generation of NADPH. Therefore, we evaluated the role of IDH2 in acrolein-induced lung injury using idh2 short hairpin RNA (shRNA)-transfected Lewis lung carcinoma (LLC) cells and idh2-deficient (idh2–/–) mice. Downregulation of idh2 expression increased susceptibility to acrolein via induction of apoptotic cell death due to elevated mitochondrial oxidative stress. Idh2 deficiency also promoted acrolein-induced lung injury in idh2 knockout mice through the disruption of mitochondrial redox status. In conclusion, idh2 deficiency leads to mitochondrial redox environment deterioration, which causes acrolein-mediated apoptosis of LLC cells and acrolein-induced lung injury in idh2–/– mice. The present study supports the central role of idh2 deficiency in inducing oxidative stress resulting from acrolein-induced disruption of mitochondrial redox status in the lung.
Highlights
Acrolein is a ubiquitous environmental pollutant that arises from cigarette smoke, incomplete combustion of plastic materials, and pyrolyzed animal and vegetable; it is endogenously produced during inflammation or oxidation of unsaturated lipids [1]
Suppression of idh2 expression led to disruption of mitochondrial redox status, induction of apoptosis, and acute injury in the lung of idh2-deficient mice and idh2 short hairpin RNA- transfected cells. These results suggest that attenuation or deficiency of idh2 leads to increased mitochondrial reactive oxygen species (ROS) levels that causes acrolein-mediated apoptosis of Lewis lung carcinoma (LLC) cells and acrolein-induced lung injury in idh2−/− mice
LLC cells were transfected with short hairpin RNA- (shRNA-)encoding LVs targeting the transcript of murine idh2 and were assayed to endogenously generate small RNA that mediates silencing of idh2
Summary
Acrolein is a ubiquitous environmental pollutant that arises from cigarette smoke, incomplete combustion of plastic materials, and pyrolyzed animal and vegetable; it is endogenously produced during inflammation or oxidation of unsaturated lipids [1]. Acrolein inhalation results in the induction of gene regulation, inflammation, and lung cell apoptosis and necrosis [1]. It has been reported that acrolein causes oxidative stress by inducing, directly or indirectly, the production of excessive reactive oxygen species (ROS) that promote cellular apoptosis [4, 5]. ROS play a important role in acrolein-induced cellular damage because acrolein is one of the most reactive α,β-unsaturated aldehyde products of lipid peroxidation [6, 7]. As an α,β-unsaturated aldehyde, acrolein contains a highly reactive carbonyl group and an electrophilic α-carbon that is highly reactive to cellular nucleophiles, such as proteins, DNA, and RNA [7]. Depletion of cellular reduced glutathione (GSH) by the formation of GS-acrolein conjugates results in increased oxidative stress [9,10,11]. Acrolein can deplete protein thiols, such as thioredoxin and glutaredoxin, which are important antioxidant proteins [12, 13]
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