Aberrant reactive aldehyde detoxification by aldehyde dehydrogenase-2 influences endometriosis development and pain-associated behaviors

McAllister, Stacy L.; Sinharoy, Pritam; Vasu, M. A.; Gross, Eric R.

doi:10.1097/j.pain.0000000000001949

Cited by 12 publications

(8 citation statements)

References 66 publications

(40 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Importantly, we also showed that the ALDH2 activation with Alda-1 is sufficient to prevent 4-HNE-induced nociception. This is in agreement with the previously report that Alda-1 administration induces analgesia in multiple pain models, associated with a significant reduction of 4-HNE adducts [9,12,13].…”

Section: Discussionsupporting

confidence: 94%

“…We previously demonstrated that accumulation of 4-HNE plays a major role in the establishment and progression of pain [ 9 ]. Elevated 4-HNE levels were also found in carrageenan-induced inflammation [ 9 ], endometriosis [ 12 ], spinal cord injury (SCI) [ 13 ], experimental autoimmune encephalomyelitis (EAE) [ 14 ] and migraine [ 15 ]. Mechanistically, 4-HNE can form protein adducts with cysteine, histidine, and lysine residues in proteins via Michael addition; therefore, causing inhibition of protein function and generating pain [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Activation of PKCε-ALDH2 Axis Prevents 4-HNE-Induced Pain in Mice

et al. 2021

View full text Add to dashboard Cite

Protein kinase Cε (PKCε) is highly expressed in nociceptor neurons and its activation has been reported as pro-nociceptive. Intriguingly, we previously demonstrated that activation of the mitochondrial PKCε substrate aldehyde dehydrogenase-2 (ALDH2) results in anti-nociceptive effects. ALDH2 is a major enzyme responsible for the clearance of 4-hydroxy-2-nonenal (4-HNE), an oxidative stress byproduct accumulated in inflammatory conditions and sufficient to induce pain hypersensitivity in rodents. Here we determined the contribution of the PKCε-ALDH2 axis during 4-HNE-induced mechanical hypersensitivity. Using knockout mice, we demonstrated that PKCε is essential for the nociception recovery during 4-HNE-induced hypersensitivity. We also found that ALDH2 deficient knockin mice display increased 4-HNE-induced nociceptive behavior. As proof of concept, the use of a selective peptide activator of PKCε (ΨεHSP90), which favors PKCε translocation to mitochondria and activation of PKCε-ALDH2 axis, was sufficient to block 4-HNE-induced hypersensitivity in WT, but not in ALDH2-deficient mice. Similarly, ΨεHSP90 administration prevented mechanical hypersensitivity induced by endogenous production of 4-HNE after carrageenan injection. These findings provide evidence that selective activation of mitochondrial PKCε-ALDH2 axis is important to mitigate aldehyde-mediated pain in rodents, suggesting that ΨεHSP90 and small molecules that mimic it may be a potential treatment for patients with pain.

show abstract

Section: Discussionsupporting

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Activation of PKCε-ALDH2 Axis Prevents 4-HNE-Induced Pain in Mice

et al. 2021

View full text Add to dashboard Cite

show abstract

“…The tissue specific distribution of ALDH2 puts the cardiovascular system, with less distribution and enzymatic activity relative to other organs, at a greater susceptibility for the reactive aldehyde-induced damage to e-cigarette aerosol which is amplified by carrying the ALDH2*2 genetic variant. Differences in tissue specific expression and activity of ALDH2 may lead to specific organ systems being more susceptible to organ injury from aldehydes [50,51]. Similar to our findings, a recent non-biased approach to map the proteome of the human body for 32 different organs measured from 14 individuals revealed the liver had ~2-fold higher ALDH2 protein expression relative to the heart [52].…”

Section: Discussionsupporting

confidence: 87%

E-cigarette aerosol exacerbates cardiovascular oxidative stress in mice with an inactive aldehyde dehydrogenase 2 enzyme

Zeng

Xiao

Chen

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

AimsE-cigarette aerosol containing aldehydes, including acetaldehyde, are metabolized by the enzyme aldehyde dehydrogenase 2 (ALDH2). However, little is known how aldehyde exposure from e-cigarettes, when coupled with an inactivating ALDH2 genetic variant, ALDH2*2 (present in 8% of the world population), affects cardiovascular oxidative stress. The aim of this study was to determine how e-cigarette aerosol exposure, when coupled with genetics, impacts cardiovascular oxidative stress in wild type ALDH2 and ALDH2*2 knock-in mice.Methods and ResultsUsing selective ion flow mass spectrometry, we determined that e-cigarette aerosol contains acetaldehyde that are 10-fold higher than formaldehyde or acrolein. Next, using wild type ALDH2 and ALDH2*2 knock-in rodents, we identified organ-specific differences in ALDH2 with the heart having ~1.5-fold less ALDH2 enzyme activity relative to the liver and lung. In isolated cardiac myocytes, acetaldehyde exposure (30 seconds, 0.1-1 μM) caused a 4-fold greater peak in calcium levels for ALDH2*2 relative to ALDH2 cardiomyocytes. ALDH2*2 cardiomyocytes exposed to acetaldehyde also demonstrated a 2-fold increase in ROS production and 2.5-fold increase in 4HNE protein adducts relative to ALDH2 cardiomyocytes. For intact rodents, ALDH2*2 knock-in mice exposed to e-cigarette aerosol had an increased heart rate beginning 5 days after exposure compared to wild type ALDH2 mice (775±30 bpm versus 679±33 bpm, respectively, *p<0.01, n=7-8/group). E-cigarette aerosol exposure also exacerbated oxidative stress in ALDH2*2 heart homogenates, including a 1.3-fold higher protein carbonyl level, a 1.7-fold higher lipid peroxide level and 1.5-fold greater phosphorylation of NF-κB relative to wild type ALDH2 homogenates.ConclusionsThe increased oxidative stress from e-cigarette aerosol aldehydes triggers the proinflammatory NF-κB pathway. As ALDH2 expression and activity is lower in the heart relative to the lung, the heart could be more susceptible to increases in cardiovascular oxidative stress from e-cigarette aerosol; particularly for those carrying an ALDH2*2 genetic variant which limits acetaldehyde metabolism.Graphical AbstractE-cigarette aerosol exposure triggers increases in ROS that lead to increased protein carbonylation, MDA production, and elevates phosphorylated NF-kB. This exposure to e-cigarette aerosol leads to increases in cardiovascular oxidative stress. For the ALDH2*2 variant, there is limited ability to metabolize the reactive aldehydes from e-cigarette aerosol and with increased levels of oxidative stress at baseline relative to wild type ALDH2, e-cigarette aerosol increased oxidative stress, protein carbonylation, and phosphorylation of NF-kB relative to wild type ALDH2 rodents.

show abstract

“…The tissue specific distribution of ALDH2 puts the cardiovascular system, with less distribution and enzymatic activity relative to other organs, at a greater susceptibility for the reactive aldehyde-induced damage to e-cigarette aerosol which is amplified by carrying the ALDH2*2 genetic variant. Differences in tissue specific expression and activity of ALDH2 may lead to specific organ systems being more susceptible to organ injury from aldehydes [ 53 , 54 ]. Similar to our findings, a recent non-biased approach to map the proteome of the human body for 32 different organs measured from 14 individuals revealed the liver had ∼2-fold higher ALDH2 protein expression relative to the heart [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

E-cigarette aerosol exacerbates cardiovascular oxidative stress in mice with an inactive aldehyde dehydrogenase 2 enzyme

Zeng

Xiao

et al. 2022

Redox Biology

Self Cite

View full text Add to dashboard Cite

Aberrant reactive aldehyde detoxification by aldehyde dehydrogenase-2 influences endometriosis development and pain-associated behaviors

Abstract: Supplemental Digital Content is Available in the Text. ALDH2 activity influences endometriosis and its associated pain.

Cited by 12 publications

References 66 publications

Activation of PKCε-ALDH2 Axis Prevents 4-HNE-Induced Pain in Mice

Activation of PKCε-ALDH2 Axis Prevents 4-HNE-Induced Pain in Mice

E-cigarette aerosol exacerbates cardiovascular oxidative stress in mice with an inactive aldehyde dehydrogenase 2 enzyme

E-cigarette aerosol exacerbates cardiovascular oxidative stress in mice with an inactive aldehyde dehydrogenase 2 enzyme

Contact Info

Product

Resources

About