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

Aims: E-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 Results: Using 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 (30seconds, 0.1-1μM) 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±30bpm versus 679±33bpm, respectively, *p<0.01, n=7-8 per 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. Conclusions: The 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.

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Abstract 491: E-cigarette Aerosol Elevates Cardiovascular Oxidative Stress in Mice With Aldehyde Dehydrogenase 2 Deficiency

Circulation Research ◽

10.1161/res.127.suppl_1.491 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Xuan Yu ◽

Xiaocong Zeng ◽

Ri Chen ◽

Pritam Sinharoy ◽

Eric R Gross

Keyword(s):

Oxidative Stress ◽

Heart Rate ◽

Aldehyde Dehydrogenase ◽

Whole Body ◽

Protein Carbonyls ◽

Wild Type ◽

Aldehyde Dehydrogenase 2 ◽

Maximal Increase ◽

Reactive Aldehydes ◽

Reactive Aldehyde

Introduction: E-cigarette aerosol contains reactive aldehydes including acetaldehyde, formaldehyde, and acrolein when e-cigarette is heated. Approximately 560 million people worldwide cannot efficiently metabolize aldehydes present in e-cigarette aerosol, due to a genetic deficiency in aldehyde dehydrogenase 2 enzyme (ALDH2), known as ALDH2*2. Little is known how aldehyde exposure from e-cigarettes, coupled with genetic differences in aldehyde metabolism, affects cardiovascular oxidative stress both at a physiological and cellular level. Hypothesis: E-cigarette aerosol exposure will elevate heart rate and cellular oxidative stress more substantially in ALDH2*2 knock-in mice versus wild type ALDH2 mice. Methods: To measure aldehyde levels, e-cigarette Juul aerosols were collected and quantified by selective ion flow gas mass spectrometry. Further, age-matched male wild type and homozygous ALDH2*2 mice (8-10 weeks old, ~25g) were implanted with EKG telemeters. After surgical recovery, mice were paired by genotype (one wild type ALDH2 and one ALDH2*2 mice) and exposed to either Juul aerosol or room air 4 sessions per day for 10 days. For each session, 7 puffs/min were drawn for the first two minutes (a total of 14 puffs), and the whole body exposure to Juul aerosol lasted 7 minutes, continued with 23 minutes smoking-free intervals in each session. Mice EKG waveforms were recorded daily. After 10 days of exposure, heart homogenates were subjected to biochemical assays including lipid peroxidation, 4-HNE protein adduct formation, and protein carbonylation. Results: Quantification of reactive aldehyde levels in e-cigarettes revealed that Juul aerosol contained acetaldehyde (5.3±0.32 ppm), formaldehyde (0.20±0.02 ppm), and acrolein (0.09±0.01 ppm). When exposed to Juul aerosol, ALDH2*2 mice showed a maximal increase in heart rate unlike ALDH2 wild type mice (774.6±29.5 bpm versus 678.9±32.8 bpm respectively, * p <0.01, n=8) at day 6. Furthermore, heart homogenates from ALDH2*2 mice demonstrated exacerbated oxidative stress, including higher level of 4-HNE adducts (1.5-fold), protein carbonyls (1.5-fold) and lipid peroxides (2-fold) relative to hearts from wild type ALDH2 mice, when both genotype mice were exposed to Juul e-cigarette aerosol (n=4/group). Conclusions: These findings indicate e-cigarette aerosols contain reactive aldehydes, primarily acetaldehyde. A deficiency in reactive aldehyde metabolism by having an ALDH2*2 deficiency may contribute to increases in heart rate and oxidative stress within the cardiovascular system while smoking e-cigarettes.

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Aldehyde dehydrogenase 2 inhibited oxidized LDL-induced NLRP3 inflammasome priming and activation via attenuating oxidative stress

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2020.06.075 ◽

2020 ◽

Vol 529 (4) ◽

pp. 998-1004

Author(s):

Youshun Xu ◽

Qiaozhen Yuan ◽

Shengchuan Cao ◽

Sumei Cui ◽

Li Xue ◽

...

Keyword(s):

Oxidative Stress ◽

Aldehyde Dehydrogenase ◽

Nlrp3 Inflammasome ◽

Oxidized Ldl ◽

Aldehyde Dehydrogenase 2

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Aldehyde dehydrogenase 2 activity and aldehydic load contribute to neuroinflammation and Alzheimer’s disease related pathology

Acta Neuropathologica Communications ◽

10.1186/s40478-019-0839-7 ◽

2019 ◽

Vol 7 (1) ◽

Cited By ~ 4

Author(s):

Amit U. Joshi ◽

Lauren D. Van Wassenhove ◽

Kelsey R. Logas ◽

Paras S. Minhas ◽

Katrin I. Andreasson ◽

...

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Alcohol Consumption ◽

Mitochondrial Dysfunction ◽

Aldehyde Dehydrogenase ◽

Cortical Neurons ◽

Aldehyde Dehydrogenase 2 ◽

East Asians

AbstractAldehyde dehydrogenase 2 deficiency (ALDH2*2) causes facial flushing in response to alcohol consumption in approximately 560 million East Asians. Recent meta-analysis demonstrated the potential link between ALDH2*2 mutation and Alzheimer’s Disease (AD). Other studies have linked chronic alcohol consumption as a risk factor for AD. In the present study, we show that fibroblasts of an AD patient that also has an ALDH2*2 mutation or overexpression of ALDH2*2 in fibroblasts derived from AD patients harboring ApoE ε4 allele exhibited increased aldehydic load, oxidative stress, and increased mitochondrial dysfunction relative to healthy subjects and exposure to ethanol exacerbated these dysfunctions. In an in vivo model, daily exposure of WT mice to ethanol for 11 weeks resulted in mitochondrial dysfunction, oxidative stress and increased aldehyde levels in their brains and these pathologies were greater in ALDH2*2/*2 (homozygous) mice. Following chronic ethanol exposure, the levels of the AD-associated protein, amyloid-β, and neuroinflammation were higher in the brains of the ALDH2*2/*2 mice relative to WT. Cultured primary cortical neurons of ALDH2*2/*2 mice showed increased sensitivity to ethanol and there was a greater activation of their primary astrocytes relative to the responses of neurons or astrocytes from the WT mice. Importantly, an activator of ALDH2 and ALDH2*2, Alda-1, blunted the ethanol-induced increases in Aβ, and the neuroinflammation in vitro and in vivo. These data indicate that impairment in the metabolism of aldehydes, and specifically ethanol-derived acetaldehyde, is a contributor to AD associated pathology and highlights the likely risk of alcohol consumption in the general population and especially in East Asians that carry ALDH2*2 mutation.

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Alpha-Lipoic Acid Ameliorates Oxidative Stress by Increasing Aldehyde Dehydrogenase-2 Activity in Patients with Acute Coronary Syndrome

The Tohoku Journal of Experimental Medicine ◽

10.1620/tjem.229.45 ◽

2013 ◽

Vol 229 (1) ◽

pp. 45-51 ◽

Cited By ~ 21

Author(s):

Rui-Jian Li ◽

Wen-Qing Ji ◽

Jiao-Jiao Pang ◽

Jia-Li Wang ◽

Yu-Guo Chen ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Coronary Syndrome ◽

Aldehyde Dehydrogenase ◽

Lipoic Acid ◽

Alpha Lipoic Acid ◽

Aldehyde Dehydrogenase 2 ◽

Coronary Syndrome

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Aldehyde dehydrogenase 2 protects against oxidative stress associated with pulmonary arterial hypertension

Redox Biology ◽

10.1016/j.redox.2016.12.019 ◽

2017 ◽

Vol 11 ◽

pp. 286-296 ◽

Cited By ~ 22

Author(s):

Tao Xu ◽

Shuangyue Liu ◽

Tingting Ma ◽

Ziyi Jia ◽

Zhifei Zhang ◽

...

Keyword(s):

Oxidative Stress ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Aldehyde Dehydrogenase ◽

Aldehyde Dehydrogenase 2 ◽

Pulmonary Arterial

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Beneficial effects of carnosine and carnosine plus vitamin E treatments on doxorubicin-induced oxidative stress and cardiac, hepatic, and renal toxicity in rats

Human & Experimental Toxicology ◽

10.1177/0960327115597468 ◽

2015 ◽

Vol 35 (6) ◽

pp. 635-643 ◽

Cited By ~ 12

Author(s):

A Kumral ◽

M Giriş ◽

M Soluk-Tekkeşin ◽

V Olgaç ◽

S Doğru-Abbasoğlu ◽

...

Keyword(s):

Oxidative Stress ◽

Vitamin E ◽

Troponin I ◽

Antioxidant Properties ◽

Lipid Peroxide ◽

Thiobarbituric Acid ◽

Protein Carbonyl ◽

Antioxidant Enzyme Activities ◽

Diene Conjugate ◽

Beneficial Effects

Objective: Oxidative stress plays an important role in doxorubicin (DOX)-induced toxicity. Carnosine (CAR) is a dipeptide with antioxidant properties. The aim of this study was to evaluate the decreasing or preventive effect of CAR alone or combination with vitamin E (CAR + Vit E) on DOX-induced toxicity in heart, liver, and brain of rats. Methods: Rats were treated with CAR (250 mg kg−1 day−1; intraperitoneally (i.p.)) or CAR + Vit E (equals 200 mg kg−1 α-tocopherol; once every 3 days; intramuscularly) for 12 consecutive days. On the 8th day of treatment, rats were injected with a single dose of DOX (30 mg kg−1, i.p.). Serum cardiac troponin I (cTnI), urea, and creatinine levels; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities; and oxidative stress parameters in tissues were measured. We also determined thiobarbituric acid reactive substances, diene conjugate, protein carbonyl (PC), and glutathione levels and antioxidant enzyme activities. Results: DOX resulted in increased serum cTnI, ALT, AST, urea, and creatinine levels and increased lipid peroxide and PC levels in tissues. CAR or CAR + Vit E treatments led to decreases in serum cTnI levels and ALT and AST activities. These treatments reduced prooxidant status and ameloriated histopathologic findings in the examined tissues. Conclusion: Our results may indicate that CAR alone, especially in combination with Vit E, protect against DOX-induced toxicity in heart, liver, and kidney tissues of rats. This was evidenced by improved cardiac, hepatic, and renal markers and restoration of the prooxidant state and amelioration of histopathologic changes.

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N-acetylcysteine and taurine prevent hyperglycemia-induced insulin resistance in vivo: possible role of oxidative stress

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00355.2002 ◽

2003 ◽

Vol 285 (4) ◽

pp. E744-E753 ◽

Cited By ~ 145

Author(s):

C. Andrew Haber ◽

Tony K. T. Lam ◽

Zhiwen Yu ◽

Neehar Gupta ◽

Tracy Goh ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

High Glucose ◽

Muscle Protein ◽

Fold Increase ◽

Protein Carbonyl ◽

Protein Carbonyl Content ◽

High Concentrations

Exposure to high concentrations of glucose and insulin results in insulin resistance of metabolic target tissues, a characteristic feature of type 2 diabetes. High glucose has also been associated with oxidative stress, and increased levels of reactive oxygen species have been proposed to cause insulin resistance. To determine whether oxidative stress contributes to insulin resistance induced by hyperglycemia in vivo, nondiabetic rats were infused with glucose for 6 h to maintain a circulating glucose concentration of 15 mM with and without coinfusion of the antioxidant N-acetylcysteine (NAC), followed by a 2-h hyperinsulinemic-euglycemic clamp. High glucose (HG) induced a significant decrease in insulin-stimulated glucose uptake [tracer-determined disappearance rate (Rd), control 41.2 ± 1.7 vs. HG 32.4 ± 1.9 mg · kg–1 · min–1, P < 0.05], which was prevented by NAC (HG + NAC 45.9 ± 3.5 mg · kg–1 · min–1). Similar results were obtained with the antioxidant taurine. Neither NAC nor taurine alone altered Rd. HG caused a significant (5-fold) increase in soleus muscle protein carbonyl content, a marker of oxidative stress that was blocked by NAC, as well as elevated levels of malondialdehyde and 4-hydroxynonenal, markers of lipid peroxidation, which were reduced by taurine. In contrast to findings after long-term hyperglycemia, there was no membrane translocation of novel isoforms of protein kinase C in skeletal muscle after 6 h. These data support the concept that oxidative stress contributes to the pathogenesis of hyperglycemia-induced insulin resistance.

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