INT158864

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Context Info
Confidence 0.58
First Reported 2006
Last Reported 2010
Negated 1
Speculated 0
Reported most in Body
Documents 25
Total Number 28
Disease Relevance 10.92
Pain Relevance 3.81

This is a graph with borders and nodes. Maybe there is an Imagemap used so the nodes may be linking to some Pages.

mitochondrion (Aldh2) oxidoreductase activity (Aldh2)
Anatomy Link Frequency
hearts 4
testis 1
aorta 1
endothelia 1
Aldh2 (Mus musculus)
Pain Link Frequency Relevance Heat
agonist 28 99.68 Very High Very High Very High
tolerance 755 98.92 Very High Very High Very High
Potency 95 98.04 Very High Very High Very High
Angina 78 92.84 High High
addiction 12 89.88 High High
Kinase C 36 82.64 Quite High
Bioavailability 21 71.32 Quite High
alcohol 110 68.40 Quite High
Inflammation 27 66.56 Quite High
antagonist 8 8.88 Low Low
Disease Link Frequency Relevance Heat
Diabetes Complications 16 99.92 Very High Very High Very High
Stress 529 99.78 Very High Very High Very High
Diabetes Mellitus 328 99.28 Very High Very High Very High
Coronary Artery Disease 48 99.00 Very High Very High Very High
Disease 52 98.94 Very High Very High Very High
Heart Disease 64 98.82 Very High Very High Very High
Cv Unclassified Under Development 192 98.26 Very High Very High Very High
Sprains And Strains 32 97.92 Very High Very High Very High
Cardiovascular Disease 93 94.12 High High
Myocardial Infarction 165 94.04 High High

Sentences Mentioned In

Key: Protein Mutation Event Anatomy Negation Speculation Pain term Disease term
It is likely that the benefit of ALDH2 activation is to facilitate the removal of cytotoxic aldehydes, such as 4-HNE and others that accumulate during ischaemia and reperfusion.9,32,62,63 4-HNE has been shown to be a substrate as well as a potent inhibitor of ALDH2 (due to 4-HNE adduct formation on ALDH264,65).
Negative_regulation (inhibitor) of ALDH2 associated with cv unclassified under development
1) Confidence 0.58 Published 2010 Journal Cardiovascular Research Section Body Doc Link PMC2936126 Disease Relevance 0.38 Pain Relevance 0.04
In the light of the ALDH2-dependent bioactivation of nitroglycerin in Asians carrying the E487K mutation, it is predicted that the substantially diminished ALDH2 activity would lead to a decreased response to nitroglycerin treatment.
Negative_regulation (diminished) of ALDH2
2) Confidence 0.58 Published 2010 Journal Cardiovascular Research Section Body Doc Link PMC2936126 Disease Relevance 0.37 Pain Relevance 0.20
Because the Asian ALDH2*2 mutation may be associated with a higher risk of various diseases including ischaemic damage9,13 due to a significant loss of ALDH2 activity, the consequence of nitroglycerin tolerance in the background of E487K polymorphism needs to be further investigated.
Negative_regulation (loss) of ALDH2 associated with tolerance and disease
3) Confidence 0.58 Published 2010 Journal Cardiovascular Research Section Body Doc Link PMC2936126 Disease Relevance 0.32 Pain Relevance 0.17
In fact, using the same ALDH2-null mice, Wenzel et al.86 demonstrated that the loss of ALDH2 enzyme activity led to increased mitochondrial oxidative stress in aortic endothelia by three pro-oxidant stimuli, nitroglycerin, doxorubicin, and acetaldehyde (Figure 1).
Negative_regulation (loss) of ALDH2 in endothelia associated with stress
4) Confidence 0.58 Published 2010 Journal Cardiovascular Research Section Body Doc Link PMC2936126 Disease Relevance 0.62 Pain Relevance 0.03
Aldehydes induce inactivation of a number of macromolecules including the proteasome, the electron transport chain (ETC) in the mitochondria, as well as inactivation of ALDH2 itself.
Negative_regulation (inactivation) of ALDH2
5) Confidence 0.58 Published 2010 Journal Cardiovascular Research Section Body Doc Link PMC2936126 Disease Relevance 0.55 Pain Relevance 0
However, the 4-HNE-induced inhibition of ALDH2 activity was completely prevented in the presence of Alda-1.9 As anticipated, following ischaemia and reperfusion, the accumulation of 4-HNE–protein adducts was lower in hearts treated with Alda-1, relative to vehicle-treated controls.9 The ability of Alda-1 to reduce cardiac damage is therefore likely due to a combination of direct enzyme activation of ALDH2 and prevention of ALDH2 inactivation by its reactive substrate, 4-HNE, which is formed and accumulates under oxidative stress (Figure 1).
Negative_regulation (inactivation) of ALDH2 in hearts associated with stress and cv unclassified under development
6) Confidence 0.43 Published 2010 Journal Cardiovascular Research Section Body Doc Link PMC2936126 Disease Relevance 0.66 Pain Relevance 0.03
However, the 4-HNE-induced inhibition of ALDH2 activity was completely prevented in the presence of Alda-1.9 As anticipated, following ischaemia and reperfusion, the accumulation of 4-HNE–protein adducts was lower in hearts treated with Alda-1, relative to vehicle-treated controls.9 The ability of Alda-1 to reduce cardiac damage is therefore likely due to a combination of direct enzyme activation of ALDH2 and prevention of ALDH2 inactivation by its reactive substrate, 4-HNE, which is formed and accumulates under oxidative stress (Figure 1).
Negative_regulation (inactivation) of ALDH2 in hearts associated with stress and cv unclassified under development
7) Confidence 0.43 Published 2010 Journal Cardiovascular Research Section Body Doc Link PMC2936126 Disease Relevance 0.66 Pain Relevance 0.03
As described above, activation of ALDH2 reduced cardiac damage caused by ischaemia insult, indicating a cardioprotective role for ALDH2.9 That study also demonstrated that inactivation of ALDH2 associated with nitroglycerin tolerance resulted in an increase in infarct size.9 These data suggest a potential risk to patients who experience an AMI while on continuous nitroglycerin treatment (Figure 1).
Negative_regulation (inactivation) of ALDH2 associated with cv unclassified under development, tolerance and myocardial infarction
8) Confidence 0.43 Published 2010 Journal Cardiovascular Research Section Body Doc Link PMC2936126 Disease Relevance 0.31 Pain Relevance 0.18
In rabbit aorta made tolerant by large doses of nitroglycerin, ALDH2 dehydrogenase activity was inhibited by ?
Negative_regulation (inhibited) of ALDH2 in aorta
9) Confidence 0.43 Published 2010 Journal Cardiovascular Research Section Body Doc Link PMC2936126 Disease Relevance 0.27 Pain Relevance 0.17
However, the 4-HNE-induced inhibition of ALDH2 activity was completely prevented in the presence of Alda-1.9 As anticipated, following ischaemia and reperfusion, the accumulation of 4-HNE–protein adducts was lower in hearts treated with Alda-1, relative to vehicle-treated controls.9 The ability of Alda-1 to reduce cardiac damage is therefore likely due to a combination of direct enzyme activation of ALDH2 and prevention of ALDH2 inactivation by its reactive substrate, 4-HNE, which is formed and accumulates under oxidative stress (Figure 1).
Negative_regulation (inhibition) of ALDH2 in hearts associated with stress and cv unclassified under development
10) Confidence 0.43 Published 2010 Journal Cardiovascular Research Section Body Doc Link PMC2936126 Disease Relevance 0.47 Pain Relevance 0.03
A drug that can increase the potency of nitroglycerin either by enhancing its bioconversion to NO and/or by preventing the inhibitory effect of nitroglycerin on ALDH2 will clearly be beneficial, especially for the ALDH2*2 human subjects.


Negative_regulation (effect) of ALDH2 associated with potency
11) Confidence 0.42 Published 2010 Journal Cardiovascular Research Section Body Doc Link PMC2936126 Disease Relevance 0.53 Pain Relevance 0.11
Particularly relevant to cardiac disease, the use of nitroglycerin (GTN) can further contribute to ALDH2 inactivation, thus decreasing the cell's natural ability to reduce ROS-induced aldehydic load and cytotoxicity.
Negative_regulation (inactivation) of ALDH2 associated with heart disease
12) Confidence 0.42 Published 2010 Journal Cardiovascular Research Section Body Doc Link PMC2936126 Disease Relevance 0.54 Pain Relevance 0
In the present study we could demonstrate that GTN treatment resulted in an increase in mitochondrial ROS and a decrease in ALDH-2 activity in the Mn-SOD+/- mice whereas PETN did not significantly alter these parameters (Figure 2 and Results).


Negative_regulation (decrease) of ALDH-2
13) Confidence 0.42 Published 2006 Journal BMC Cardiovasc Disord Section Body Doc Link PMC1654181 Disease Relevance 0.43 Pain Relevance 0.18
It is thought that GTN induces mitochondrial ROS formation which may contribute to oxidative inhibition of ALDH-2 activity and depletion of reduced thiols (such as dihydrolipoic acid) [38] thereby disrupting the physiological catalytic cycle (Figure 4).
Negative_regulation (inhibition) of ALDH-2
14) Confidence 0.42 Published 2006 Journal BMC Cardiovasc Disord Section Body Doc Link PMC1654181 Disease Relevance 0.13 Pain Relevance 0.08
To clarify the mechanism underlying the lower TCA levels, we measured expression of the ALDH2 protein involved in the metabolism of chloral hydrate to TCA because TRI has been reported to inhibit ALDH expression and activity (Wang et al. 1999); we found that ALDH2 was reduced to the same degree after TRI exposure in all three strains of mice.
Negative_regulation (reduced) of ALDH2 associated with sprains and strains
15) Confidence 0.41 Published 2010 Journal Environ Health Perspect Section Body Doc Link PMC2974693 Disease Relevance 0.29 Pain Relevance 0.05
Recent studies have revealed that mitochondrial reactive oxygen species (ROS) formation and a subsequent oxidative inactivation of nitrate reductase, the mitochondrial aldehyde dehydrogenase (ALDH-2), play an important role in the development of nitrate and cross-tolerance.
Negative_regulation (inactivation) of ALDH-2 associated with tolerance
16) Confidence 0.33 Published 2009 Journal Pharmacol Rep Section Abstract Doc Link 19307691 Disease Relevance 0.56 Pain Relevance 0.36
An interesting link between mitochondrial oxidative stress triggered ALDH-2 inhibition and activation of vascular NADPH oxidases could be the accumulation of toxic aldehydes (as observed in ALDH-2-/- mice).
Negative_regulation (inhibition) of ALDH-2 associated with stress
17) Confidence 0.31 Published 2006 Journal BMC Cardiovasc Disord Section Body Doc Link PMC1654181 Disease Relevance 0.31 Pain Relevance 0.26
GTN in vivo treatment decreased the redox-sensitive ALDH-2 activity in isolated heart mitochondria from Mn-SOD+/- mice (30.4 ± 1.5 in ethanol group vs. 21.4 ± 1.5 in GTN group, n = 25–27, p < 0.001) whereas PETN slightly (although not significantly) increased the ALDH-2 activity (39.8 ± 3.3 in DMSO group vs. 42.3 ± 4.4 in PETN group, n = 9, p = 0.647).


Negative_regulation (decreased) of ALDH-2 in heart
18) Confidence 0.31 Published 2006 Journal BMC Cardiovasc Disord Section Body Doc Link PMC1654181 Disease Relevance 0 Pain Relevance 0
According to recent studies, mitochondrial ROS formation and oxidative inactivation of the organic nitrate bioactivating enzyme mitochondrial aldehyde dehydrogenase (ALDH-2) play an important role for the development of nitrate and cross-tolerance.


Negative_regulation (inactivation) of ALDH-2 associated with tolerance
19) Confidence 0.31 Published 2006 Journal BMC Cardiovasc Disord Section Abstract Doc Link PMC1654181 Disease Relevance 0.07 Pain Relevance 0.22
Chronic GTN infusion lead to impaired vascular responses to GTN and acetylcholine (ACh), increased the ROS formation in mitochondria and decreased ALDH-2 activity in Mn-SOD+/- mice.
Negative_regulation (decreased) of ALDH-2
20) Confidence 0.31 Published 2006 Journal BMC Cardiovasc Disord Section Abstract Doc Link PMC1654181 Disease Relevance 0.13 Pain Relevance 0.33

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