Aldehyde dehydrogenase 2 overexpression inhibits neuronal apoptosis after spinal cord ischemia/reperfusion injury

Aldehyde dehydrogenase 2（ALDH2）is an important factor in inhibiting oxidative stress and has been shown to protect against renal ischemia/reperfusion injury.Therefore,we hypothesized that ALDH_2 could reduce spinal cord ischemia/reperfusion injury.Spinal cord ischemia/reperfusion injury was induced in rats using the modified Zivin＇s method of clamping the abdominal aorta.After successful model establishment,the agonist group was administered a daily consumption of 2.5%alcohol.At 7 days post-surgery,the Basso,Beattie,and Bresnahan score significantly increased in the agonist group compared with the spinal cord ischemia/reperfusion injury group.ALDH_2expression also significantly increased and the number of apoptotic cells significantly decreased in the agonist group than in the spinal cord ischemia/reperfusion injury group.Correlation analysis revealed that ALDH_2 expression negatively correlated with the percentage of TUNEL-positive cells（r=-0.485,P〈0.01）.In summary,increased ALDH_2 expression protected the rat spinal cord against ischemia/reperfusion injury by inhibiting apoptosis.

Aldehyde dehydrogenase 2 preserves mitochondrial morphology and attenuates hypoxia/reoxygenationinduced cardiomyocyte injury

BACKGROUND:Disturbance of mitochondrial fi ssion and fusion(termed mitochondrial dynamics)is one of the leading causes of ischemia/reperfusion(I/R)-induced myocardial injury.Previous studies showed that mitochondrial aldehyde dehydrogenase 2(ALDH2)conferred cardioprotective effect against myocardial I/R injury and suppressed I/R-induced excessive mitophagy in cardiomyocytes.However,whether ALDH2 participates in the regulation of mitochondrial dynamics during myocardial I/R injury remains unknown.METHODS:In the present study,we investigated the effect of ALDH2 on mitochondrial dynamics and the underlying mechanisms using the H9c2 cells exposed to hypoxia/reoxygenation(H/R)as an in vitro model of myocardial I/R injury.RESULTS:Cardiomyocyte apoptosis was significantly increased after oxygen-glucose deprivation and reoxygenation(OGD/R),and ALDH2 activation largely decreased the cardiomyocyte apoptosis.Additionally,we found that both ALDH2 activation and overexpression significantly inhibited the increased mitochondrial fission after OGD/R.Furthermore,we found that ALDH2 dominantly suppressed dynamin-related protein 1(Drp1)phosphorylation(Ser616)and adenosine monophosphate-activated protein kinase(AMPK)phosphorylation(Thr172)but not interfered with the expression levels of mitochondrial shaping proteins.CONCLUSIONS:We demonstrate the protective effect of ALDH2 against cardiomyocyte H/R injury with a novel mechanism on mitochondrial fission/fusion.

Chronic stress causes protein kinase C epsilon-aldehyde dehydrogenase 2 signaling pathway perturbation in the rat hippocampus and prefrontal cortex,but not in the myocardium

Chronic stress is strongly associated with the occurrence and development of depression and cardiovascular disease.Stress can induce altered mitochondrial function and activation of apoptosis in the cardio-cerebral system.However,it is unknown whether the protein kinase C ε（PKCε）-aldehyde dehydrogenase 2（ALDH2） pathway is altered under chronic stress,and this study sought to address this question.A rat model of depression was established using a chronic unpredictable mild stress（CUMS） protocol.After experiencing CUMS for 4 weeks,the sucrose preference test and the forced swim test verified depressive-like behaviors.Enzyme linked immunosorbent assays showed that ALDH2 activity was decreased in the rat hippocampus and prefrontal cortex,but was not altered in the myocardium.Western blot assays demonstrated reduced levels of ALDH2 and PKCε,but increased levels of 4-hydroxy-2-nonenal（4 HNE） adducts.Caspase-3 expression did not obviously alter,but active forms of caspase-3 were increased in the hippocampus and prefrontal cortex.In the myocardium,expression of ALDH2,PKCε and 4 HNE adducts did not remarkably alter;while caspase-3 expression was reduced and the active forms of caspase-3 were upregulated.Pearson＇s correlation test demonstrated that expression of 4 HNE adducts was positively correlated with levels of the active forms of caspase-3 in the hippocampus and prefrontal cortex,but not in the myocardium.In conclusion,chronic stress can damage the PKCε-ALDH2 signaling pathway in the hippocampus and prefrontal cortex,but not in the myocardium.Moreover,4 HNE is associated with active forms of caspase-3 in the hippocampus and prefrontal cortex.

Effect of Aldehyde Dehydrogenase 2 Gene Polymorphism on Hemodynamics After Nitroglycerin Intervention in Northern Chinese Han Population

Background：Nitroglycerin （NTG） is one of the few immediate treatments for acute angina.Aldehyde dehydrogenase 2 （ALDH2） is a key enzyme in the human body that facilitates the biological metabolism of NTG.The biological mechanism of NTG serves an important function in NTG efficacy.Some reports still contradict the results that the correlation between ALDH2 gene polymorphisms and NTG and its clinical efficacy is different.However,data on NTG measurement by pain relief are subjective.This study aimed to investigate the influence ofALDH2 gene polymorphism on intervention with sublingual NTG using noninvasive hemodynamic parameters of cardiac output （CO） and systemic vascular resistance （SVR） in Northern Chinese Han population.Methods：This study selected 559 patients from the Affiliated Hospital of Qingdao University.A total of 203 patients presented with coronary heart disease （CHD） and 356 had non-CHD （NCHD） cases.All patient ALDH2 genotypes （G504A） were detected and divided into two types：Wild （GG） and mutant （GA/AA）.Among the CHD group,103 were wild-type cases,and 100 were mutant-type cases.Moreover,196 cases were wild-type,and 160 cases were mutant type among the NCHD volunteers.A noninvasive hemodynamic detector was used to monitor the CO and the SVR at the 0,5,and 15 minute time points after medication with 0.5 mg sublingual NTG.Two CO and SVR indicators were used for a comparative analysis of all case genotypes.Results：Both CO and SVR indicators significantly differed between the wild and mutant genotypes at various time points after intervention with sublingual NTG at 5 and 15 minutes in the NCHD （F =16.460,15.003,P =0.000,0.000） and CHD groups （F =194.482,60.582,P =0.000,0.000）.All CO values in the wild-type case of both NCHD and CHD groups increased,whereas those in the mutant type decreased.The CO and △CO differences were statistically significant （P 〈 0.05; P 〈 0.05）.The SVR and △SVR changed between the wild-and mutant-type cases at all-time points in both NCHD and CHD groups had statistically significant differences （P 〈 0.05; P 〈 0.05）.Conclusion：ALDH2 （G504A） gene polymorphism is associated with changes in noninvasive hemodynamic parameters （i.e.CO and SVR） after intervention with sublingual NTG.This gene polymorphism may influence the effect of NTG intervention on Northern Chinese Han population.

Association between Carotid Intima-media Thickness and Aldehyde Dehydrogenase 2 Glu504Lys Polymorphism in Chinese Han with Essential Hypertension

Background： Aldehyde dehydrogenase 2 （ALDH2） is involved in the pathophysiological processes of cardiovascular diseases. Recent studies showed that mutant ALDH2 could increase oxidative stress and is a susceptible factor for hypertension. In addition, wild-type ALDH2 could improve the endothelial functions, therefore reducing the risk of developing atherosclerosis. The aim of the present study was to explore the frequency of the Glu504Lys polymorphism of the ALDH2 gene and its relation to carotid intima-media thickness （CIMT） in a group of patients with essential hypertension （EH） and to investigate the association between the Glu504Lys polymorphism and CIMT in Chinese Han patients with EH. Methods： In this study, 410 Chinese Han patients with EH who received physical examinations at the People＇s Hospital of Sichuan Province （China） were selected. DNA microarray chip was used for the genotyping of the Glu504Lys polymorphism of the ALDH2 gene. The differences in CIMT among patients with different Glu504Lys ALDH2 genotypes were analyzed. Results： The mean CIMT of the patients carrying AA/AG and GG genotypes was 1.02 ± 0.31 mm and 0.78 ±0.28 mm, respectively. One-way ANOVA showed that the CIMT of the patients carrying the AA/AG genotype was significantly higher than in the ones carrying the GG genotype （P 〈 0.001）. Multivariate logistic regression showed that the Glu504Lys AA/AG genotype of the ALDH2 gene was one of the major factors influencing the CIMT in patients with EH （odds ratio = 3.73 l, 95% confidence interval = 1.589-8.124, P = 0.001）. Conclusions： The Glu504Lys polymorphism of the ALDH2 gene is associated with the CIMT of Chinese Han patients with EH in Sichuan, China.

Association of genetic polymorphisms of aldehyde dehydrogenase-2 with esophageal squamous cell dysplasia

AIM:To demonstrate the possible associations between genetic polymorphisms of aldehyde dehydrogenase-2(ALDH2) and esophageal squamous cell dysplasia(ESCD).METHODS:All participants came from an area of high incidence of esophageal cancer and underwent an endoscopic staining examination;biopsies were taken from a non-staining area of the mucosa and diagnosed by histopathology.Based on the examinations,the subjects were divided into the control group with normal esophageal squamous epithelial cells and the ESCD group.ALDH2 genotypes of 396 cases were determined including 184 ESCD cases and 212 controls.The odds ratio(OR) and 95% confidence intervals(95% CI) were calculated by binary logistic regression models.RESULTS:The distribution of ALDH2 genotypes showed significant differences between the two groups.The adjustment factors were gender and age in the logistic regression models.Compared with 2*2/2*2 genotype,2*1/2*1 genotype was found to be a risk factor for ESCD,and the OR(95% CI) was 4.50(2.21-9.19).There were significant correlations between ALDH2 genotypes and alcohol drinking/smoking/history of esophageal cancer.CONCLUSION:The ALDH2 polymorphism is significantly associated with ESCD.

Risks of incident heart failure with preserved ejection fraction in Chinese patients hospitalized for cardiovascular diseases

Background Endogenous aldehyde damages DNA and potentiates an ageing phenotype. The aldehyde dehydrogenase 2(ALDH2) rs671 polymorphism has a prevalence of 30%–50% in Asian populations. In this study, we aimed to analyze risk factors contributing to the development of heart failure with preserved ejection fraction(HFpEF) along with the genetic exposure in Chinese patients hospitalized with cardiovascular diseases(CVD). Methods From July 2017 to October 2018, a total of 770 consecutive Chinese patients with normal left ventricular ejection fractions(LVEF) and established CVD(hypertension, coronary heart diseases, or diabetes) were enrolled in this prospective cross-sectional study. HFpEF was defined by the presence of at least one of symptom(dyspnoea and fatigue) or sign(rales and ankle swelling) related to heart failure;N-terminal pro-B-Type natriuretic peptide(NT pro-BNP ≥ 280 pg/mL);LVEF ≥ 50%;and at least one criterion related to elevated ventricular filling pressure or diastolic dysfunction(left atrial diameter > 40 mm, E/E’ ≥ 13, E’/A’ < 1 or concurrent atrial fibrillation). Logistic regression was performed to yield adjusted odds ratios(ORs) for HFp EF incidence associated with traditional and/or genetic exposures. Results Finally, among 770 patients with CVD, 92(11.9%) patients were classified into the HFpEF group according to the diagnostic criteria. The mean age of the participants was 67 ± 12 years, and 278(36.1%) patients were females. A total of 303(39.4%) patients were ALDH2*2 variant carriers. In the univariate analysis, eight exposures were found to be associated with HFpEF: atrial fibrillation, ALDH2*2 variants, hypertension, age, anaemia, smoking, alcohol consumption and sex. Multivariable logistic regression showed that 4 ‘A’ variables(atrial fibrillation, ALDH2*2 variants, age and anaemia) were significantly associated with an increased risk of HFpEF. Atrial fibrillation was associated with a 3.8-fold increased HFpEF risk(95% CI: 2.21–6.61, P < 0.001), and the other three exposures associated with increased HFpEF risk were the ALDH2*2 variant(OR = 2.41, 95% CI: 1.49–3.87, P < 0.001), age(OR = 2.14, 95% CI: 1.27–3.60, P = 0.004), and anaemia(OR = 1.79, 95% CI: 1.05–3.03, P = 0.032). These four variables predicted HFpEF incidence in Chinese CVD patients(C-statistic = 0.745, 95% CI: 0.691–0.800, P < 0.001). Conclusions 4 A traits(atrial fibrillation, ALDH2*2 variants, age and anaemia) were associated with an increased risk of HFpEF in Chinese CVD patients. Our results provide potential clues to the aetiology, pathophysiology and therapeutic targets of HFpEF.

Role of ALDH2 in Hepatic Disorders: Gene Polymorphism and Disease Pathogenesis

Aldehyde dehydrogenase 2(ALDH2)is a key enzyme of alcohol metabolism and it is involved in the cellular mechanism of alcohol liver disease.ALDH2 gene mutations exist in about 8%of the world’s population,with the incidence reaching 45%in East Asia.The mutations will result in impairment of enzyme activity and accumulation of acetaldehyde,facilitating the progression of other liver diseases,including non-alcoholic fatty liver diseases,viral hepatitis and hepatocellular carcinoma,through adduct formation and inflammatory responses.In this review,we seek to summarize recent research progress on the correlation between ALDH2 gene polymorphism and multiple liver diseases,with an attempt to provide clues for better understanding of the disease mechanism and for strategy making.