Decreased expression of mitochondrial aldehyde dehydrogenase-2 induces liver injury via activation of the mitogen-activated protein kinase pathway

Abstract

SummaryThe aim of this study was to determine the role of ALDH2 in the injury of liver from brain-dead donors. Using brain-dead rabbit model and hypoxia model, levels of ALDH2 and apoptosis in tissues and cell lines were determined by Western blot, flow cytometry (FCM), and transferase (TdT)-mediated biotin-16-dUTP nick-end labeling (TUNEL) assays. After the expression of ALDH2 during hypoxia had been inhibited or activated, the accumulations of 4-hydroxynonenal (4-HNE) and molecules involved in mitogen-activated protein kinase (MAPK) signaling pathway were analyzed using ELISA kit and Western blot. The low expression of phosphorylated ALDH2 in liver was time-dependent in the braindead rabbit model. Immunohistochemistry showed ALDH2 was primarily located in endothelial, and the rates of cell apoptosis in the donation after brain-death (DBD) rabbit groups significantly increased with time. Following the treatment of inhibitor of ALDH2, daidzein, in combination with hypoxia for 8 h, the apoptosis rate and the levels of 4-HNE, P-JNK, and cleaved caspase-3 significantly increased in contrast to that in hypoxic HUVECs; however, they all decreased after treatment with Alda-1 and hypoxia compared with that in hypoxic HUVECs (P < 0.05). Instead, the levels of P-P38, P-ERK, P-JNK, and cleaved caspase-3 decreased and the ratio of bcl-2/bax increased with ad-ALDH2 (10 6 pfu/ml) in combination with hypoxia for 8 h, which significantly alleviated in contrast to that in hypoxic HUVECs. We found low expression of ALDH2 and high rates of apoptosis in the livers of brain-dead donor rabbits. Furthermore, decreased ALDH2 led to apoptosis in HUVECs through MAPK pathway.

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

“…This effect has been suggested to occur through the inhibition of Akt, which increases the Bax/Bcl-2 ratio and activates a caspase-3 apoptotic cascade[ 43 , 44 ]. This Akt inhibition in the presence of 4-HNE can be totally reversed by using an ALDH2 agonist, such as Alda-1[ 45 ]. Further investigations have evidenced that increased ALDH2 expression through Alda-1 treatment protects I/R-induced brain cell necrosis and apoptosis[ 16 , 24 ].…”

“…Besides these benefits of ALDH2 observed in the heart and brain, benefits have also been shown for limiting neuronal apoptosis in spinal cord IRI[ 24 ]. Recently, Zhong et al[ 45 ] reported that low ALDH2 promotes liver apoptosis through the MAPK pathway when ALDH2 agonists are used, in which ALDH2 action is not only based on the 4-HNE clearance ratio, but also on its subsidiary involvement in controlling indirect 4-HNE pathways.…”

ALDH 2 conferred neuroprotection on cerebral ischemic injury by alleviating mitochondria-related apoptosis through JNK/caspase-3 signing pathway

“…Several studies described that 4-HNE was regulated by c-Jun N-terminal protein kinase (JNK) indirectly, which functioned like signaling molecules, or directly by the kinase's active domains. JNK modulated the rate of cells and mediated neuronal injury in different ischemic models [51,52]. Since 4-HNE is a substrate of ALDH2, it is reasonable to hypothesize that ALDH2 mediates JNK activation.…”

Protective effect of Letinous�edodes foot peptides against ethanol‑induced liver injury in L02 cells

“…However, if the activity change is not timely for the oxidation of acetaldehyde to acetic acid, the damage to the liver cells will be more serious compared with ethanol. If ADH activity is inhibited, the ethanol hazard for the body itself will increase (28,29). ALDH is also an important enzyme in ethanol metabolism, as it can transform toxic acetaldehyde associated with alcoholic liver injury into acetic acid, which is a nontoxic metabolic product.…”