Alda-1, an ALDH2 activator, protects against hepatic ischemia/reperfusion injury in rats via inhibition of oxidative stress

Abstract

Previous studies have proved that activation of aldehyde dehydrogenase two (ALDH2) can attenuate oxidative stress through clearance of cytotoxic aldehydes, and can protect against cardiac, cerebral, and lung ischemia/reperfusion (I/R) injuries. In this study, we investigated the effects of the ALDH2 activator Alda-1 on hepatic I/R injury. Partial warm ischemia was performed in the left and middle hepatic lobes of Sprague-Dawley rats for 1 h, followed by 6 h of reperfusion. Rats received either Alda-1 or vehicle by intravenous injection 30 min before ischemia. Blood and tissue samples of the rats were collected after 6-h reperfusion. Histological injury, proinflammatory cytokines, reactive oxygen species (ROS), cellular apoptosis, ALDH2 expression and activity, 4-hydroxy-trans-2-nonenal (4-HNE) and malondialdehyde (MDA) were measured. BRL-3A hepatocytes were subjected to hypoxia/reoxygenation (H/R). Cell viability, ROS, and mitochondrial membrane potential were determined. Pretreatment with Alda-1 significantly alleviated I/R-induced elevations of alanine aminotransferase and aspartate amino transferase, and significantly blunted the pathological injury of the liver. Moreover, Alda-1 significantly inhibited ROS and proinflammatory cytokines production, 4-HNE and MDA accumulation, and apoptosis. Increased ALDH2 activity was found after Alda-1 administration. No significant changes in ALDH2 expression were observed after I/R. ROS was also higher in H/R cells than in control cells, which was aggravated upon treatment with 4-HNE, and reduced by Alda-1 treatment. Cell viability and mitochondrial membrane potential were inhibited in H/R cells, which was attenuated upon Alda-1 treatment. Activation of ALDH2 by Alda-1 attenuates hepatic I/R injury via clearance of cytotoxic aldehydes.

Endothelial Aldehyde Dehydrogenase 2 as a Target to Maintain Vascular Wellness and Function in Ageing

“…The direct anti-oxidative properties are assumed to depend on its potent reductase function with its highly activated sulfhydryl groups [27]. In addition to oxidative capabilities, ALDH2 possesses nitrate reductase activity responsible for the bioconversion of nitroglycerin to 1,2-glyceryl dinitrate (GDN), thus inducing NO release [28][29][30]. ALDH2 protein can be the substrate of various post-translational modifications, including oxidation, S-nitrosylation, phosphorylation, nitration, acetylation, glycosylation, and adduct formation, most of which reduce its activity [31].…”

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

“…Previous experimental evidence demonstrated that JNK signaling pathway was an upstream mediator of ischemic damage induced apoptosis through the control of caspase-3 activation [24,25]. Moreover, ALDH2 is crucial in the regulation of ROS generation [26,27]. ALDH2 deficiency leads to elevation of ROS levels [28].…”

The role of aldehyde dehygrogenase 2 in liver injury caused by vinyl chloride and high-fat diet.

“…This conclusion is a concern for occupational exposure and residential populations living in close proximity to VC-contaminated sites. VC directly impairs hepatic mitochondrial electron transport chain independent of diet (45,78). In this section, we hypothesize that VC will also affect mitochondrial ALDH2, an enzyme that has previously shown to be protective.…”

“…It is suggested that this is a compensated upregulation of protein expression in response to inhibition of the enzymatic activity caused by increased aldehyde toxicity. It is also known that ɛPKC translocation mediated by HFD-induced ROS production in mitochondria is a direct activator of ALDH2 expression (78).…”

“…This model allowed us a better understanding of the underlying mechanisms in the interaction of VC and obesity, which provided the rationale for determining a target to protect the liver from injury. ALDH2 is a mitochondrial enzyme known for its role in ethanol metabolism and its participation in protecting organs from not only alcohol but also other stress (78). The effect of ALDH2 in the interaction of VC and HFD induced liver injury remains elusive.…”