Mitochondrial Aldehyde Dehydrogenase Activity Research Articles

Activation of mitochondrial aldehyde dehydrogenase 2 promotes hair growth in human hair follicles

IntroductionHair loss is a common phenomenon associated with various environmental and genetic factors. Mitochondrial dysfunction-induced oxidative stress has been recognized as a crucial determinant of hair follicle (HF) biology. Aldehyde dehydrogenase 2 (ALDH2) mitigates oxidative stress by detoxifying acetaldehyde. This study investigated the potential role of ALDH2 modulation in HF function and hair growth promotion. ObjectivesTo evaluate the effects of ALDH2 activation on oxidative stress in HFs and hair growth promotion. MethodsThe modulatory role of ALDH2 on HFs was investigated using an ALDH2 activator. ALDH2 expression in human HFs was evaluated through in vitro immunofluorescence staining. Ex vivo HF organ culture was employed to assess hair shaft elongation, while the fluorescence probe 2′,7′- dichlorodihydrofluorescein diacetate was utilized to detect reactive oxygen species (ROS). An in vivo mouse model was used to determine whether ALDH2 activation induces anagen. ResultsDuring the anagen phase, ALDH2 showed significantly higher intensity than that in the telogen phase, and its expression was primarily localized along the outer layer of HFs. ALDH2 activation promoted anagen phase induction by reducing ROS levels and enhancing reactive aldehyde clearance, which indicated that ALDH2 functions as a ROS scavenger within HFs. Moreover, ALDH2 activation upregulated Akt/GSK 3β/β-catenin signaling in HFs. ConclusionsOur findings highlight the hair growth promotion effects of ALDH2 activation in HFs and its potential as a promising therapeutic approach for promoting anagen induction.

Pretreatment with the ALDH2 activator Alda‑1 protects rat livers from ischemia/reperfusion injury by inducing autophagy.

Hepatic ischemia/reperfusion injury (HIRI) is a complex pathophysiological process that often leads to poor clinical prognosis. Clinically, the effective means to alleviate HIRI are limited. The aim of the present study was to investigate whether Alda-1, an activator of mitochondrial aldehyde dehydrogenase 2 (ALDH2), had a protective effect on HIRI and to investigate the mechanisms underlying this protective effect. Sprague-Dawley rats were treated with Alda-1 or Daidzin, an ALDH2 inhibitor, 30 min before partial (70%) warm liver ischemia to induce HIRI. The 48 rats were randomly divided into four groups: Sham, ischemia injury (IR), IR-Alda-1, and IR-Daidzin. After 6 and 24 h of reperfusion, serum and liver tissue samples were collected and stored for further experiments. Alanine aminotransferase, aspartate aminotransferase and hematoxylin & eosin staining was used to evaluate the liver damage. Western blotting and reverse transcription-quantitative PCR were used to detect the expression of related proteins and mRNA. TUNEL staining was used to observe the apoptosis of liver cells. Transmission electron microscopy was used to detect the mitochondrial injuries. Alda-1 pretreatment ameliorated the HIRI-induced damage to the liver function and reduced histological lesions. Alda-1 also increased ALDH2 activity after HIRI. Moreover, the pretreatment with Alda-1 reduced the accumulation of toxic aldehyde 4-hydroxy-2-nonenal, decreased the production of reactive oxygen species and malondialdehyde, reversed the damage to the liver mitochondria, attenuated hepatocyte apoptosis and inhibited the HIRI-induced inflammatory response, including high-mobility group box 1/toll-like receptor 4 signaling. Alda-1 also induced autophagy by upregulating autophagy-related 7 and Rab7 increasing the microtubule associated protein 1 light chain 3 αII/I ratio and inhibiting p62 expression. ALDH2-induced autophagy was dependent on the activation of the AKT/mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) signaling pathways. In conclusion, the findings of the present study suggested that Alda-1 may protect the liver against HIRI-induced damage, including hepatic enzyme injury, acetaldehyde accumulation, oxidative stress, hepatocyte apoptosis and inflammation. Alda-1 may confer this protection by inducing autophagy through the AKT/mTOR and AMPK signaling pathways. Therefore, ALDH2 could represent a potential pharmacological target in the clinical treatment of HIRI.

Alda-1, an activator of ALDH2, ameliorates Achilles tendinopathy in cellular and mouse models

Achilles tendinopathy has a high re-injury rate and poor prognosis. Development of effective therapy for Achilles tendinopathy is important. Excessive accumulation of ROS and resulting oxidative stress are believed to cause tendinopathy. Overproduction of hydrogen peroxide (H2O2), the most common ROS, could lead to the tendinopathy by causing oxidative damage, activation of endoplasmic reticulum (ER) stress and apoptotic death of tenocytes. Activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) is expected to alleviate oxidative stress and ER stress. Alda-1 is a selective and potent activator of ALDH2. In this study, we examined the cytoprotective benefit of Alda-1, an activator of ALDH2, on H2O2-induced Achilles tendinopathy in cellular and mouse models. We prepared cellular and mouse models of Achilles tendinopathy by treating cultured Achilles tenocytes and Achilles tendons with oxidative stressor H2O2. Subsequently, we studied the protective benefit of Alda-1 on H2O2-induced Achilles tendinopathy. Alda-1 pretreatment attenuated H2O2-induced cell death of cultured Achilles tenocytes. Treatment of Alda-1 prevented H2O2-induced oxidative stress and depolarization of mitochondrial membrane potential in tenocytes. Application of Alda-1 attenuated H2O2-triggered mitochondria- and ER stress-mediated apoptotic cascades in cultured tenocytes. Alda-1 treatment ameliorated the severity of H2O2-induced Achilles tendinopathy in vivo by preventing H2O2-induced pathological histological features of Achilles tendons, apoptotic death of Achilles tenocytes and upregulated expression of inflammatory cytokines IL-1β and TNF-α. Our results provide the evidence that ALDH2 activator Alda-1 ameliorates H2O2-induced Achilles tendinopathy. Alda-1 could be used for preventing and treating Achilles tendinopathy.

Neuroprotective Effects of Pomegranate Juice against Parkinson's Disease and Presence of Ellagitannins-Derived Metabolite-Urolithin A-In the Brain.

Pomegranate juice is a rich source of ellagitannins (ETs) believed to contribute to a wide range of pomegranate’s health benefits. While a lot of experimental studies have been devoted to Alzheimer disease and hypoxic-ischemic brain injury, our knowledge of pomegranate’s effects against Parkinson’s disease (PD) is very limited. It is suggested that its neuroprotective effects are mediated by ETs-derived metabolites—urolithins. In this study, we examined the capability of pomegranate juice for protection against PD in a rat model of parkinsonism induced by rotenone. To evaluate its efficiency, assessment of postural instability, visualization of neurodegeneration, determination of oxidative damage to lipids and α-synuclein level, as well as markers of antioxidant defense status, inflammation, and apoptosis, were performed in the midbrain. We also check the presence of plausible active pomegranate ETs-derived metabolite, urolithin A, in the plasma and brain. Our results indicated that pomegranate juice treatment provided neuroprotection as evidenced by the postural stability improvement, enhancement of neuronal survival, its protection against oxidative damage and α-synuclein aggregation, the increase in mitochondrial aldehyde dehydrogenase activity, and maintenance of antiapoptotic Bcl-xL protein at the control level. In addition, we have provided evidence for the distribution of urolithin A to the brain.

Mitochondrial 4-HNE derived from MAO-A promotes mitoCa2+ overload in chronic postischemic cardiac remodeling

Chronic remodeling postmyocardial infarction consists in various maladaptive changes including interstitial fibrosis, cardiomyocyte death and mitochondrial dysfunction that lead to heart failure (HF). Reactive aldehydes such as 4-hydroxynonenal (4-HNE) are critical mediators of mitochondrial dysfunction but the sources of mitochondrial 4-HNE in cardiac diseases together with its mechanisms of action remain poorly understood. Here, we evaluated whether the mitochondrial enzyme monoamine oxidase-A (MAO-A), which generates H2O2as a by-product of catecholamine metabolism, is a source of deleterious 4-HNE in HF. We found that MAO-A activation increased mitochondrial ROS and promoted local 4-HNE production inside the mitochondria through cardiolipin peroxidation in primary cardiomyocytes. Deleterious effects of MAO-A/4-HNE on cardiac dysfunction were prevented by activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2), the main enzyme for 4-HNE metabolism. Mechanistically, MAO-A-derived 4-HNE bound to newly identified targets VDAC and MCU to promote ER-mitochondria contact sites and MCU higher-order complex formation. The resulting mitochondrial Ca2+ accumulation participated in mitochondrial respiratory dysfunction and loss of membrane potential, as shown with the protective effects of the MCU inhibitor, RU360. Most interestingly, these findings were recapitulated in a chronic model of ischemic remodeling where pharmacological or genetic inhibition of MAO-A protected the mice from 4-HNE accumulation, MCU oligomer formation and Ca2+ overload, thus mitigating ventricular dysfunction. To our knowledge, these are the first evidences linking MAO-A activation to mitoCa2+ mishandling through local 4-HNE production, contributing to energetic failure and postischemic remodeling.

A small-molecule activator of mitochondrial aldehyde dehydrogenase 2 reduces the severity of cerulein-induced acute pancreatitis

Acute pancreatitis (AP) is one of the leading causes of hospital admission for gastrointestinal disorders. Although lipid peroxides are produced in AP, it is unknown if targeting lipid peroxides prevents AP. This study aimed to investigate the role of mitochondrial aldehyde dehydrogenase 2 (ALDH2), a critical enzyme for lipid peroxide degradation, in AP and the possible underlying mechanisms. Cerulein was used to induce AP in C57BL/6 J male mice and pancreatic acinar cells were used to elucidate underlying mechanisms in vitro. Pancreatic enzymes in the serum, lipid peroxidation products malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), and Bcl-2, Bax and cleaved caspase-3 were measured. ALDH2 activation with a small-molecule activator, Alda-1, reduced the levels of the pancreatic enzymes in the serum and the lipid peroxidation products MDA and 4-HNE. In addition, Alda-1 decreased Bax and cleaved caspase-3 expression and increased Bcl-2 expression in vivo and in vitro. In conclusion, ALDH2 activation by Alda-1 has a protective effect in cerulein-induced AP by mitigating apoptosis in pancreatic acinar cells by alleviating lipid peroxidation.

Activation of mitochondrial aldehyde dehydrogenase (ALDH2) by ALDA-1 reduces both the acquisition and maintenance of ethanol intake in rats: A dual mechanism?

A number of pre-clinical studies have shown that brain-generated acetaldehyde, the first metabolite of ethanol, exerts reinforcing effects that promote the acquisition of ethanol intake, while chronic intake maintenance appears to be mediated by alcohol-induced brain neuroinflammation/oxidative stress. Recently, it was described that N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide (ALDA-1) activates aldehyde dehydrogenase-2 (ALDH2), enzyme that catalyzes the oxidation of ethanol-derived acetaldehyde to acetate. The aim of this study was to determine the effects of ALDA-1 on both the acquisition and the maintenance of alcohol intake in alcohol-preferring UChB rats. For ethanol acquisition studies, naïve UChB rats were treated with five daily doses of ALDA-1 (12.5, 25 or 50 mg/kg, i.p.) from one day before the start of ethanol exposure. For chronic intake studies, UChB rats exposed for 98 days to a free access to 10% ethanol and water were treated daily with ALDA-1 (12.5, 25 or 50 mg/kg, i.p.) for five days. The administration of ALDA-1 reduced by 72–90% (p < 0.001) the acquisition of ethanol consumption in naïve rats. At chronic ethanol consumption, ALDA-1 reduced ethanol intake by 61–82% (p < 0.001). ALDA-1 administration increased by 3- and 2.3-fold the activity of ALDH2 in brain and liver, respectively. ALDA-1 did not affect saccharin consumption, nor it modified the rate of ethanol elimination. The study shows that the activation of ALDH2 by ALDA-1 is effective for inhibiting both the acquisition and the maintenance of chronic ethanol intake by alcohol-preferring rats. Thus, the activation of brain ALDH2 may constitute a novel approach in the treatment of alcohol use disorders.

Activator of Mitochondrial Aldehyde Dehydrogenase (Alda-1) Could Enhance Quality of Equine Cooled Semen by Ameliorating Loss of Mitochondrial Function Over Time

Equine sperm energy metabolism is mainly dependent on mitochondrial oxidative phosphorylation, causing abundant production of reactive oxygen species (ROS). Reacting with fatty acids, ROS result in formation of aldehydes, which diminish sperm viability and motility. Aldehyde dehydrogenases are responsible for removal of aldehydes. Aldehyde dehydrogenase(Alda-1) is the activator of mitochondrial aldehyde dehydrogenase and has been shown to alleviate the detrimental effects of aldehydes in different tissues. The present study was conducted to evaluate the influence of Alda-1 on cooled stallion semen over a 72-hour period. Motility was evaluated using computer-assisted sperm analysis. Viability, mitochondrial membrane potential, and superoxide anion production were assessed using flow cytometry–based methods by SYBR14 plus propidium iodine, JC-1, and dihydroethidium, respectively. Adenosine triphosphate (ATP) content was measured using a luciferase-based ATP bioluminescent assay. Preliminarily, 50 μM dose of Alda-1 was found to be effective on equine cooled semen based on the greater progressive motility observed after exposure to 50 μM Alda-1 as compared with control group (P < .05). Furthermore, it was revealed that Alda-1 (50 μM) ameliorated the decrease in viability, motility, velocity, mitochondrial membrane potential, and ATP production during 72-hour preservation of equine cooled semen (P < .05). In addition, proportion of sperm positive for superoxide anion was higher in Alda-1 than the control group (P < .05), which was interpreted as positive impact of Alda-1 on sperm mitochondrial respiration. In conclusion, the present study showed that Alda-1 could enhance cooling preservation of equine semen by maintaining mitochondrial function and mitigating reduction in ATP generation, motility, and viability over time.

Baicalin protects H9c2 cardiomyocytes against hypoxia/reoxygenation-induced apoptosis and oxidative stress through activation of mitochondrial aldehyde dehydrogenase 2.

Baicalin, a flavonoid glycoside separated from Scutellaria baicalensis, has cardioprotection against ischaemia/reperfusion (I/R) injury. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is considered as an endogenous protective mechanism against I/R injury depending on its anti-oxidant and anti-apoptotic characteristics. The present study demonstrates whether ALDH2 contributes to the cardioprotection of baicalin against hypoxia/reoxygenation (H/R)-inudced H9c2 cardiomyocytes injury. Our results observed that H/R treatment resulted in a significant decrease in cells viability and obvious increases in caspase-3 activity and apoptosis rate in H9c2 cells, while these alterations were evidently reversed by baicalin pretreatment. Simultaneously, baicalin mitigated H/R-induced the decreases in the levels of ALDH2 mRNA and protein as well as the activity of ALDH2 in H9c2 cells. However, we found that daidzin, an ALDH2 antagonist, remarkably attenuated baicalin-elicited inhibitory action on H/R-induced the downregulation of cells viability and Bcl-2 protein expression, and the upregulations of caspase-3 activity, apoptosis rate, cytochrome c and Bax proteins expressions in H9c2 cells. In addition, baicalin reversed H/R-induced oxidative stress as evidenced by the downregulation of malondialdehyde (MAD) and 4-hydroxy aldehydes (4-HNE) levels, the inhibition of endogenous reactive oxygen species (ROS) generation, and the downregulation of superoxide dismutase (SOD) activity induced by H/R treatment, while these effects were also blocked by daidzin. Furthermore, we found that Alda-1, an ALDH2 agonist, also abolished H/R-induced cytotoxicity, apoptosis, and oxidative stress, indicating that ALDH2 mediated H/R-induced H9c2 cell injury. Overall, these results suggested that baicalin prevents H/R-induced apoptosis and oxidative stress through enhancing ALDH activity and expression in H9c2 cardiomyocytes.

Alda-1 Protects Against Acrolein-Induced Acute Lung Injury and Endothelial Barrier Dysfunction.

Inhalation of acrolein, a highly reactive aldehyde, causes lung edema. The underlying mechanism is poorly understood and there is no effective treatment. In this study, we demonstrated that acrolein not only dose-dependently induced lung edema but also promoted LPS-induced acute lung injury. Importantly, acrolein-induced lung injury was prevented and rescued by Alda-1, an activator of mitochondrial aldehyde dehydrogenase 2. Acrolein also dose-dependently increased monolayer permeability, disrupted adherens junctions and focal adhesion complexes, and caused intercellular gap formation in primary cultured lung microvascular endothelial cells (LMVECs). These effects were attenuated by Alda-1 and the antioxidant N-acetylcysteine, but not by the NADPH inhibitor apocynin. Furthermore, acrolein inhibited AMP-activated protein kinase (AMPK) and increased mitochondrial reactive oxygen species levels in LMVECs-effects that were associated with impaired mitochondrial respiration. AMPK total protein levels were also reduced in lung tissue of mice and LMVECs exposed to acrolein. Activation of AMPK with 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside blunted an acrolein-induced increase in endothelial monolayer permeability, but not mitochondrial oxidative stress or inhibition of mitochondrial respiration. Our results suggest that acrolein-induced mitochondrial dysfunction may not contribute to endothelial barrier dysfunction. We speculate that detoxification of acrolein by Alda-1 and activation of AMPK may be novel approaches to prevent and treat acrolein-associated acute lung injury, which may occur after smoke inhalation.

Proteomic Analysis of Mitochondria-Enriched Fraction Isolated from the Frontal Cortex and Hippocampus of Apolipoprotein E Knockout Mice Treated with Alda-1, an Activator of Mitochondrial Aldehyde Dehydrogenase (ALDH2).

The role of different genotypes of apolipoprotein E (apoE) in the etiology of Alzheimer’s disease is widely recognized. It has been shown that altered functioning of apoE may promote 4-hydroxynonenal modification of mitochondrial proteins, which may result in mitochondrial dysfunction, aggravation of oxidative stress, and neurodegeneration. Mitochondrial aldehyde dehydrogenase (ALDH2) is an enzyme considered to perform protective function in mitochondria by the detoxification of the end products of lipid peroxidation, such as 4-hydroxynonenal and other reactive aldehydes. The goal of our study was to apply a differential proteomics approach in concert with molecular and morphological techniques to elucidate the changes in the frontal cortex and hippocampus of apolipoprotein E knockout (apoE−/−) mice upon treatment with Alda-1—a small molecular weight activator of ALDH2. Despite the lack of significant morphological changes in the brain of apoE−/− mice as compared to age-matched wild type animals, the proteomic and molecular approach revealed many changes in the expression of genes and proteins, indicating the impairment of energy metabolism, neuroplasticity, and neurogenesis in brains of apoE−/− mice. Importantly, prolonged treatment of apoE−/− mice with Alda-1 led to the beneficial changes in the expression of genes and proteins related to neuroplasticity and mitochondrial function. The pattern of alterations implies mitoprotective action of Alda-1, however, the accurate functional consequences of the revealed changes require further research.

Human Second Window Pre-Conditioning and Post-Conditioning by Nitrite Is Influenced by a Common Polymorphism in Mitochondrial Aldehyde Dehydrogenase

Pre-conditioning is an exciting physiological phenomenon that, despite great efforts, has so far resisted translation to mainstream clinical medicine. Many potential triggers (e.g., ischemia of the organ in question or a remote organ, many different drugs) have been investigated, but recent work has implicated activation of mitochondrial aldehyde dehydrogenase (ALDH2) as central to the process. A genetic polymorphism, known as ALDH2*2, is common worldwide (present in up to 40% of Han Chinese people) and produces a functionally different enzyme. The authors used a variety of protocols in the human ischemic forearm model, in participants with both enzyme types, to assess cytoprotection with low-dose sodium nitrite and attempt to further elucidatethe role of ALDH2.

Electrophilic aldehyde products of lipid peroxidation selectively adduct to heat shock protein 90 and arylsulfatase A in stallion spermatozoa.

Oxidative stress is a major determinant of mammalian sperm function stimulating lipid peroxidation cascades that culminate in the generation of potentially cytotoxic aldehydes. The aim of this study was to assess the impact of such aldehydes on the functionality of stallion spermatozoa. The impact of exposure to exogenous acrolein (ACR) and 4-hydroxynonenal (4HNE) was manifested in a highly significant dose- and time-dependent increase in mitochondrial reactive oxygen species (ROS), total cellular ROS, a decrease in sperm motility, and a time-dependent increase in lipid peroxidation. Notably, low doses of ACR and 4HNE also caused a significant decrease in zona binding. In contrast, exogenous malondialdehyde, a commonly used marker of oxidative stress, had little impact on the various sperm parameters assessed. In accounting for the negative physiological impact of ACR and 4HNE, it was noted that both aldehydes readily adducted to sperm proteins located predominantly within the head, proximal centriole, and tail. The detoxifying activity of mitochondrial aldehyde dehydrogenase 2 appeared responsible for a lack of adduction in the midpiece; however, this activity was overwhelmed by 24 h of electrophilic aldehyde exposure. Sequencing of the dominant proteins targeted for ACR and 4HNE covalent modification identified heat shock protein 90 alpha (cytosolic) class A member 1 and arylsulfatase A, respectively. These collective findings may prove useful in the identification of diagnostic biomarkers of stallion fertility and resolving the mechanistic basis of sperm dysfunction in this species.

Aldehyde dehydrogenase 2 deficiency negates chronic low-to-moderate alcohol consumption-induced cardioprotecion possibly via ROS-dependent apoptosis and RIP1/RIP3/MLKL-mediated necroptosis

Previous studies evidenced the beneficial effects of low-to-moderate alcohol consumption on cardiovascular system by activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2), a key enzyme metabolizing acetaldehyde to innocuous acetic acid, in diabetic mice. It remains questionable whether people with inactive ALDH2 would also benefit from the drinking habit. Present study was therefore designed to examine the influence of ALDH2 deficiency on low-to-moderate alcohol consumption related myocardial alternations. Wildtype (WT) and ALDH2 knockout (KO) mice were exposed to low-to-moderate alcohol (EtOH) challenge for 6weeks. Cardiac function and cell death related pathways were then measured. Although EtOH exposure did not further improve cardiac function or reduce reactive oxygen species (ROS) levels in WT mice, levels of high density lipoprotein-cholesterol (HDL-c) and expression of heme oxygenase-1 (HO-1) were significantly elevated in WT-EtOH group. However, EtOH exposure in KO mice depressed cardiac function as indicated by reduced left ventricular ejection fraction (EF) and increased myocardial fibrosis deposition as well as the excessive ROS accumulation. Above changes were related to altered cell demise (apoptosis and necroptosis), as shown by upregulated expression of cleaved caspase 9, cleaved caspase 3 and RIP1/RIP3/MLKL cascade. Our results thus suggest that ALDH2 is indispensable for the favorable cardiac effect of low-to-moderate alcohol consumption and ALDH2 deficiency may lead to unexpected cardiac dysfunctions via enhancing myocardial apoptosis and necroptosis.

Mitochondrial aldehyde dehydrogenase activity protects against lipopolysaccharide‑induced cardiac dysfunction in rats.

Myocardial dysfunction in sepsis is associated with an increased risk of mortality. The mitochondrial aldehyde dehydrogenase (ALDH2) enzyme is crucial for protecting the heart from ischemic injury. The aim of the present study was to determine the role of ALDH2 in cardiac dysfunction induced by lipopolysaccharide (LPS). Male rats were treated intraperitoneally with LPS, and their stroke volume and cardiac output were evaluated using an M‑mode echocardiograph. The expression levels and activity of ALDH2, nitric oxide content and inducible nitric oxide synthase (iNOS) activity, and the opening of the mitochondrial permeability transition pore (MPTP) were also evaluated. Treatment with LPS (5, 10, or 20 mg/kg) resulted in a steady decrease in cardiac output and stroke volume. The ALDH2 activity was decreased in a dose‑dependent manner; however, the ALDH2 protein expression levels remained unchanged. Alda‑1, a specific activator of ALDH2, increased the activity of ALDH2 and lessened LPS‑induced cardiac dysfunction. A marked opening of the MPTP was observed 12 h following treatment with LPS, which was prevented by Alda‑1. The improvement in cardiac function in response to treatment with Alda‑1, was partially prevented by treatment with the MPTP inhibitor atractyloside. LPS treatment induced an increase in iNOS activation and inhibition of ALDH2 activity. The iNOS selective inhibitor, aminoguanidine, partially reversed the LPS‑induced ALDH2 activity decrease and MPTP opening. These results indicate that ALDH2 activity may have a role in protecting against LPS‑induced cardiac dysfunction. The potential mechanism may involve inhibition of MPTP opening and iNOS expression.

Aldehyde dehydrogenase 2 activation in heart failure restores mitochondrial function and improves ventricular function and remodelling.

We previously demonstrated that pharmacological activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) protects the heart against acute ischaemia/reperfusion injury. Here, we determined the benefits of chronic activation of ALDH2 on the progression of heart failure (HF) using a post-myocardial infarction model. We showed that a 6-week treatment of myocardial infarction-induced HF rats with a selective ALDH2 activator (Alda-1), starting 4 weeks after myocardial infarction at a time when ventricular remodelling and cardiac dysfunction were present, improved cardiomyocyte shortening, cardiac function, left ventricular compliance and diastolic function under basal conditions, and after isoproterenol stimulation. Importantly, sustained Alda-1 treatment showed no toxicity and promoted a cardiac anti-remodelling effect by suppressing myocardial hypertrophy and fibrosis. Moreover, accumulation of 4-hydroxynonenal (4-HNE)-protein adducts and protein carbonyls seen in HF was not observed in Alda-1-treated rats, suggesting that increasing the activity of ALDH2 contributes to the reduction of aldehydic load in failing hearts. ALDH2 activation was associated with improved mitochondrial function, including elevated mitochondrial respiratory control ratios and reduced H2O2 release. Importantly, selective ALDH2 activation decreased mitochondrial Ca(2+)-induced permeability transition and cytochrome c release in failing hearts. Further supporting a mitochondrial mechanism for ALDH2, Alda-1 treatment preserved mitochondrial function upon in vitro aldehydic load. Selective activation of mitochondrial ALDH2 is sufficient to improve the HF outcome by reducing the toxic effects of aldehydic overload on mitochondrial bioenergetics and reactive oxygen species generation, suggesting that ALDH2 activators, such as Alda-1, have a potential therapeutic value for treating HF patients.

Proteomic analysis of liver mitochondria of atherosclerotic apoE – knockout mice treated with Alda-1 – an activator of mitochondrial aldehyde dehydrogenase (ALDH2)

Proteomic analysis of liver mitochondria of atherosclerotic apoE – knockout mice treated with Alda-1 – an activator of mitochondrial aldehyde dehydrogenase (ALDH2)

Chronic protection against ischemia and reperfusion-induced endothelial dysfunction during therapy with different organic nitrates

Ischemic and pharmacologic preconditioning have great clinical potential, but it remains unclear whether their effects can be maintained over time during repeated exposure.We have previously demonstrated that the acute protective effect of nitroglycerin (GTN) is attenuated during repeated daily administration. Pentaerythrityl tetranitrate (PETN) is an organic nitrate with different hemodynamic and biochemical properties. The purpose of the current experiment was to study the preconditioning-like effects of PETN and GTN during repeated daily exposure. In a randomized, investigator-blind parallel trial, 30 healthy (age 25-32) volunteers were randomized to receive (1) transdermal GTN (0.6 mg/h) administered for 2 h a day for 6 days; (2) oral PETN (80 mg) once a day for 6 days; or (3) no therapy. One week later, endothelium-dependent flow-mediated dilation was assessed before and after exposure to ischemia and reperfusion (IR). IR caused a significant blunting of the endothelium-dependent relaxation in the control group (FMD before IR: 5.8 ± 2.1%; after IR 1.0 ± 2.1%; P < 0.01). Daily, 2-h exposure to GTN partially prevented IR-induced endothelial dysfunction (FMD before IR: 7.7 ± 2.4%; after IR 4.3 ± 3.0%; P < 0.01 compared to before IR). In contrast, daily PETN administration afforded greater protection from IR-induced endothelial injury (FMD before IR: 7.9 ± 1.7%; after IR 6.4 ± 5.3%, P = ns; P < 0.05 ANOVA across groups). In vitro, incubation of human endothelial cells with GTN (but not PETN) was associated with inhibition (P < 0.01) of aldehyde dehydrogenase, an enzyme that is important for both nitrate biotransformation and ischemic preconditioning. We previously showed that upon repeated administration, the preconditioning-like effects of GTN are attenuated. The present data demonstrate a gradient in the extent of protection afforded by the two nitrates, suggesting that PETN-induced preconditioning is maintained after prolonged administration in a human in vivo model of endothelial dysfunction induced by ischemia. Using isolated human endothelial cells, we propose a mechanistic explanation for this observation based on differential effects of GTN versus PETN on the activity of mitochondrial aldehyde dehydrogenase.

Activity of endogenous aldehydes catabolism enzymes in subcellular fractions of liver, heart and brain of rats at pubertal age under stress

Activities of enzymes involved in redox transformation of endogenous aldehydes have been investigated in subcellular fractions of liver, heart, and brain of pubertal rats exposed to prolonged immobilization stress. In the liver aldo-keto reductase (AKR) activity in the postmitochondrial fraction and aldehyde dehydrogenase (ALDH) acivity of the mitochondrial fraction demonstrated a more pronounced decrease in 2-month-old rats. Rat heart postmitochondrial AKR and ALDH demonstrated opposite changes in their enzymatic activities, while activity of mitochondrial ALDH remained unchanged. Brain cells create conditions that favor effective utilization of endogenous aldehydes in metabolic redox pathways.

Acetylation-dependent regulation of mitochondrial ALDH2 activation by SIRT3 mediates acute ethanol-induced eNOS activation

Moderate alcohol consumption has beneficial effects on endothelial nitric-oxide synthase (eNOS) activation, which can engender an array of anti-atherogenic actions. Here we show that in human aortic endothelial cells (HAECs), rapid activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) mediates ethanol-induced eNOS activation by preventing reactive oxygen species (ROS) accumulation. Furthermore, activation of ALDH2 by ethanol is due to its hyperacetylation by SIRT3 inactivation. These data suggest that ethanol-induced eNOS activation in HAECs may be dependent on ALDH2 hyperacetylation by SIRT3 inactivation.