Aldehyde Dehydrogenase 2 (ALDH2) in Rat Fatty Liver Cold Ischemia Injury

Abstract

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.

Polyethylene Glycol 35 as a Perfusate Additive for Mitochondrial and Glycocalyx Protection in HOPE Liver Preservation

“…Inability to generate sufficient ATP to maintain ionic homeostasis affects the integrity of the mitochondria. All these processes can be modulated by the preservation solution during cold storage in order to maintain the graft viability; for this, the presence of PEG35 is determinant, as we have previously demonstrated [47]. The presence of PEG35 in the IGL-1 solution is more effective at preventing energy metabolism failure than UW, thus favoring a better graft conservation [6].…”

“…For instance, it might be of interest to assess levels of syndecan and heparan sulphate, which would give us an insight of the status of the GCX in HOPE strategies [63][64][65][66][67][68]. Further, it would be interesting to assess mitochondrial parameters besides ALDH2 [47], such as succinate [77,78], or others that have been recently linked both to lipoperoxidation and energetic levels, such as UCP1 and UCP2 [79][80][81][82][83], which could provide relevant information, especially when steatotic livers are used (Scheme 2). The assessment of these new proposed markers involved in different critical points of different crucial pathways brought together could strengthen the informative value of the most widely used, such as transaminases.…”

Ischemia/Reperfusion Injury Revisited: An Overview of the Latest Pharmacological Strategies

“…Several protective drugs modulate other independent routes that may alternatively be activated during reperfusion and that are not assigned to the RISK, SAFE or the cGMP/PKC pathways. They can have different types of effects such as such as inhibition of ROS-producing complexes [18,67,134,135,136,137,138,139,140,141,142,143], or may act as anti-apoptotic [144], anti-inflammatory [24,53,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164] and antioxidants agents [165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194], as glucose metabolism enhancers [99,…”

A new organ preservation solution for static cold storage of the liver. Amniotic fluid

“…Cell swelling and lysis occur as a result of all these events 5 . After ischemia-reperfusion, toxic molecules are produced primarily in the form of reactive oxygen species (ROS), leading to I/R damage 5 , 30 . In our study, besides the lack of, we also did not study the oxidative stress markers.…”