Role of aldehyde dehydrogenase 2 in ischemia reperfusion injury: An update

Institut George Lopez-1 (IGL-1) and Histidine-tryptophan-ketoglutarate (HTK) solutions are proposed as alternatives to UW (gold standard) in liver preservation. Their composition differs in terms of the presence/absence of oncotic agents such as HES or PEG, and is decisive for graft conservation before transplantation. This is especially so when fatty (steatotic) livers are used since these grafts are more vulnerable to ischemia insult during conservation. Their composition determines the extent of the subsequent reperfusion injury after transplantation. Aldehyde dehydrogenase-2 (ALDH2), a mitochondrial enzyme, has been reported to play a protective role in warm ischemia-reperfusion injury (IRI), but its potential in fatty liver cold ischemic injury has not yet been investigated. We evaluated the relevance of ALDH2 activity in cold ischemia injury when fatty liver grafts from Zucker Obese rats were preserved in UW, HTK, and IGL-1 solutions, in order to study the mechanisms involved. ALDH2 upregulation was highest in livers preserved in IGL-1. It was accompanied by a decrease in transaminases, apoptosis (Caspase 3 and TUNEL assay), and lipoperoxidation, which was concomitant with the effective clearance of toxic aldehydes such as 4-hydroxy-nonenal. Variations in ATP levels were also determined. The results were consistent with levels of NF-E2 p45-related factor 2 (Nrf2), an antioxidant factor. Here we report for the first time the relevance of mitochondrial ALDH2 in fatty liver cold preservation and suggest that ALDH2 could be considered a potential therapeutic target or regulator in clinical transplantation.

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Alda-1 Ameliorates Liver Ischemia-Reperfusion Injury by Activating Aldehyde Dehydrogenase 2 and Enhancing Autophagy in Mice

Journal of Immunology Research ◽

10.1155/2018/9807139 ◽

2018 ◽

Vol 2018 ◽

pp. 1-14 ◽

Cited By ~ 3

Author(s):

Meng Li ◽

Min Xu ◽

Jichang Li ◽

Lili Chen ◽

Dongwei Xu ◽

...

Keyword(s):

Reperfusion Injury ◽

Aldehyde Dehydrogenase ◽

Inflammatory Responses ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Liver Ischemia ◽

Aldehyde Dehydrogenase 2 ◽

Serum Samples ◽

Reactive Aldehydes ◽

Key Enzyme

Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme for metabolism of reactive aldehydes, but its role during liver ischemia-reperfusion injury (IRI) remains unclear. In the present study, we investigated the effects of the ALDH2 activator, Alda-1, in liver IRI and elucidated the underlying mechanisms. Mice were pretreated with Alda-1 and subjected to a 90 min hepatic 70% ischemia model, and liver tissues or serum samples were collected at indicated time points after reperfusion. We demonstrated that Alda-1 pretreatment had a hepatoprotective role in liver IRI as evidenced by decreased liver necrotic areas, serum ALT/AST levels, and liver inflammatory responses. Mechanistically, Alda-1 treatment enhanced ALDH2 activity and subsequently reduced the accumulation of reactive aldehydes and toxic protein adducts, which result in decreased hepatocyte apoptosis and mitochondrial dysfunction. We further demonstrated that Alda-1 treatment could activate AMPK and autophagy and that AMPK activation was required for Alda-1-mediated autophagy enhancement. These findings collectively indicate that Alda-1-mediated ALDH2 activation could be a promising strategy to improve liver IRI by clearance of reactive aldehydes and enhancement of autophagy.

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