Alda-1 Attenuates Lung Ischemia-Reperfusion Injury by Reducing 4-Hydroxy-2-Nonenal in Alveolar Epithelial Cells

Ding, Jie; Zhang, Quanyi; Luo, Qipeng; Ying, Yongquan; Liu, Yiwei; Li, Yinan; Wei, Wei; Yan, Fuxia; Zhang, Hao

doi:10.1097/ccm.0000000000001563

Cited by 43 publications

(43 citation statements)

References 34 publications

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“…Our findings were consistent with the reported anti-inflammatory property of Alda-1 [17,29]. In a mouse model of lung I/R, the TNF-α and IL-1β were significantly reversed from the I/R-induced elevation to levels similar to that of control groups [17]. Similarly, in a rat model of myocardial infarction, the number of TNF-α-positive cells was significantly decreased by Alda-1 treatment [29].…”

Section: Discussionsupporting

confidence: 93%

“…In agreement with our expectation, the serum levels of TNF-α, IL-1β and IL-6 were significantly suppressed by Alda-1 treatment, paralleling the remarkably decreased morphological damage in the lung and intestine. Our findings were consistent with the reported anti-inflammatory property of Alda-1 [17,29]. In a mouse model of lung I/R, the TNF-α and IL-1β were significantly reversed from the I/R-induced elevation to levels similar to that of control groups [17].…”

Section: Discussionsupporting

confidence: 91%

“…Their findings are the first revelation about ALDH2 in I/R injury. Since then, many studies have consistently demonstrated the protective effects of Alda-1 in cardiac injury and other I/R injury models, including the brain [15], lung [17] and kidney [18]. However, its effect on gut I/R remains unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Since then, more subsequent studies have repeatedly validated the effectiveness of ALDH2 activation in cardioprotection [10–14]. Apart from its application in cardiac research, the ALDH2 agonist has also been reported to confer protection against ischaemic injury in the brain [15,16], lungs [17] and kidneys [18], through clearance of reactive aldehydes, such as 4-HNE and MDA.…”

Section: Introductionmentioning

confidence: 99%

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Pretreatment with the ALDH2 agonist Alda-1 reduces intestinal injury induced by ischaemia and reperfusion in mice

Zhu

Wang

et al. 2017

Clinical Science

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Many studies demonstrate that activation of aldehyde dehydrogenase 2 (ALDH2) protects against oxidative stress via detoxification of cytotoxic aldehydes, and could attenuate cardiac, cerebral, lung and renal ischaemia–reperfusion (I/R) injuries. However, the effect of ALDH2 in intestinal I/R is unknown. The present study was set up to determine whether an ALDH2 agonist, Alda-1, could alleviate intestinal injury after gut I/R. In a mouse model of intestinal I/R injury, histological grading, proinflammatory cytokines, oxidative stress, cellular apoptosis, chemokine contents, ALDH2 activity, 4-hydroxy-trans-2-nonenal (4-HNE) and malondialdehyde (MDA) were evaluated. The results indicated that I/R treatment conferred elevation in pathological scores, proinflammatory cytokines, oxidative stress, cellular apoptosis and chemokine levels, accompanied by accumulated 4-HNE and MDA. No significant changes in ALDH2 activity were observed after I/R. However, Alda-1 pretreatment significantly decreased these injurious indicators, concomitant with up-regulated ALDH2 activity, and lessened 4-HNE and MDA accumulation. Taken together, our results implicate activation of ALDH2 by Alda-1 in the significant abatement intestinal I/R injury.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pretreatment with the ALDH2 agonist Alda-1 reduces intestinal injury induced by ischaemia and reperfusion in mice

Zhu

Wang

et al. 2017

Clinical Science

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“…As shown in Figure 5A, both MCP-1 and ICAM-1 protein were increased after inhibiting ALDH2 activity. To determine the exact effect of ALDH2, we used Alda-1, a novel small molecule which can activate catalysis for both wild-type ALDH2 (ALDH2*1) and ALDH2*2 [25, 26], to stimulate ALDH2 activity. We demonstrated that 20μM Alda-1 increased ALDH2 activity approximately by 80% with no effect from the solvent DMSO (Figure S2B).…”

Section: Resultsmentioning

confidence: 99%

Aldehyde dehydrogenase 2 inhibits inflammatory response and regulates atherosclerotic plaque

et al. 2016

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Previous studies demonstrated that aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism, which eliminates ALDH2 activity down to 1%-6%, is a susceptibility gene for coronary disease. Here we investigated the underlying mechanisms based on our prior clinical and experimental studies. Male apoE−/− mice were transfected with GFP, ALDH2-overexpression and ALDH2-RNAi lentivirus respectively (n=20 each) after constrictive collars were placed around the right common carotid arteries. Consequently, ALDH2 gene silencing led to an increased en face plaque area, more unstable plaque with heavier accumulation of lipids, more macrophages, less smooth muscle cells and collagen, which were associated with aggravated inflammation. However, ALDH2 overexpression displayed opposing effects. We also found that ALDH2 activity decreased in atherosclerotic plaques of human and aged apoE−/− mice. Moreover, in vitro experiments with human umbilical vein endothelial cells further illustrated that, inhibition of ALDH2 activity resulted in elevating inflammatory molecules, an increase of nuclear translocation of NF-κB, and enhanced phosphorylation of NF-κB p65, AP-1 c-Jun, Jun-N terminal kinase and p38 MAPK, while ALDH2 activation could trigger contrary effects. These findings suggested that ALDH2 can influence plaque development and vulnerability, and inflammation via MAPK, NF-κB and AP-1 signaling pathways.

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Alda‐1, an aldehyde dehydrogenase‐2 agonist, causes deterioration in renal functions following ischemia–reperfusion injury due to crystalline nephropathy

Hammad

Al-Salam

Yuvaraju

et al. 2018

Drug Development Research

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Renal ischemia–reperfusion injury (IRI) induces the production of aldehydes which are detoxified by aldehyde dehydrogenases (ALDHs). Alda‐1 is a selective ALDH2 agonist and its protective effect was demonstrated in several conditions. The effect of Alda‐1 on the kidney or on renal IRI was not investigated. We investigated the effect of Alda‐1 on the renal dysfunction following IRI. Wistar rats underwent left IRI for 40 min. Group‐Alda (n = 11) received Alda‐1 starting 24 h before IRI and continued for 7 days thereafter when renal functions were measured. Group‐Vx (n = 11) underwent similar protocol but received the dissolvent. Alda‐1 did not affect renal blood flow or glomerular filtration rate in the left ischemic kidney in Group‐Alda compared to Group‐Vx (3.05 ± 0.50 vs. 3.53 ± 0.70, and 0.40 ± 0.06 vs. 0.51 ± 0.08, respectively, p > .05 for both). However, left renal fractional sodium excretion was higher in Group‐Alda (2.80 ± 0.43 vs. 1.37 ± 0.36, p = .02). Alda‐1 also adversely affected the gene expressions of kidney injury molecule‐1 and neutrophil gelatinase‐associated lipocalin (217 ± 38 vs. 99 ± 13 and 49 ± 13 vs. 20 ± 5, respectively, p < .05 for both) and the alterations in tumor necrosis factor‐α, transforming growth factor‐β1, plasminogen activator inhibitor‐1, fibronectin 1 and p53 (4.4 ± 0.9 vs. 2.1 ± 0.3, 1.5 ± 0.1 vs. 1.1 ± 0.1, 30.0 ± 2.7 vs. 11.7 ± 2.3, 3.6 ± 0.4 vs. 2.1 ± 0.2 and 1.3 ± 0.1 vs. 0.9 ± 0.07, respectively, p ≤ .05 for all). This was associated with intratubular crystal deposition suggestive of crystalline nephropathy. Alda‐1 exacerbated the IRI‐induced renal tubular dysfunction and alterations in markers of acute kidney injury, biomarkers of inflammation, fibrosis and apoptosis and this was associated with intratubular crystal deposition suggestive of crystalline nephropathy.

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Alda-1 Attenuates Lung Ischemia-Reperfusion Injury by Reducing 4-Hydroxy-2-Nonenal in Alveolar Epithelial Cells

Cited by 43 publications

References 34 publications

Pretreatment with the ALDH2 agonist Alda-1 reduces intestinal injury induced by ischaemia and reperfusion in mice

Pretreatment with the ALDH2 agonist Alda-1 reduces intestinal injury induced by ischaemia and reperfusion in mice

Aldehyde dehydrogenase 2 inhibits inflammatory response and regulates atherosclerotic plaque

Alda‐1, an aldehyde dehydrogenase‐2 agonist, causes deterioration in renal functions following ischemia–reperfusion injury due to crystalline nephropathy

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