Short‐Term Acetaldehyde Exposure Depresses Ventricular Myocyte Contraction: Role of Cytochrome P450 Oxidase, Xanthine Oxidase, and Lipid Peroxidation

Aberle, Nicholas S.; Ren, Jun

doi:10.1111/j.1530-0277.2003.tb04393.x

Cited by 37 publications

(14 citation statements)

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“…[47][48][49][50] Thus, it is possible that hypoxemia in a state of cardiomyopathy triggers the formation of acetone, which then induces CYP2E1 to enhance the metabolism of endogenous ketones to meet the energy demand of the heart. The expression of CYP2E1 increases significantly in heart diseases, [13][14][15][16][17] and here we found that the expression of CYP2E1 also increased in ADR-induced DCM heart and Lmna E82K DCM mice ( Figure 1A and 1B). The previous reports and our results suggest that the upregulation of CYP2E1 might be an important molecular event to meet the energy demand in diseased hearts.…”

Section: Discussionsupporting

confidence: 61%

“…[10][11][12] The expression level of CYP2E1 increases significantly in heart tissues in humans under ischemia; mice, rats, and dogs with dilated cardiomyopathy (DCM); and spontaneously hypertensive rats. [13][14][15][16][17][18] The overexpression of CYP2E1 is associated with several cellular markers of oxidative stress, as well as with decreased viability as a result of both necrosis and apoptosis. [19][20][21][22] Oxidative stress and apoptosis in myocytes play important roles in the pathogenesis of cardiovascular diseases, such as ischemic heart disease, atherosclerosis, cardiomyopathy, and heart failure.…”

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confidence: 99%

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Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT ^R141W Dilated Cardiomyopathy Transgenic Mice

Zhang

et al. 2012

Hypertension

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Abstract-Cytochrome P450 2E1 (CYP2E1) is a cytochrome P450 enzyme that catalyzes the metabolism of toxic substrates. CYP2E1 is upregulated in heart disease, including the dilated cardiomyopathy (DCM) mouse model. Here, knockdown of CYP2E1 significantly ameliorated the dilated left ventricle, thin wall, and dysfunctional contraction in the cTnT R141W and adriamycin-induced DCM mouse models. Interstitial fibrosis, poorly organized myofibrils, and swollen mitochondria with loss of cristae were improved in the myocardium of ␣-myosin heavy chain (MHC)-cTnT R141W ϫCYP2E1-silence double-transgenic mice when compared with the cTnT R141W transgenic mice. Oxidative stress, the activation of caspase 3 and caspase 9, the release of cytochrome c, and the apoptosis in the myocardium were significantly decreased in double-transgenic mice compared with the cTnT R141W transgenic mice. In summary, the expression of CYP2E1 is upregulated in heart disease and might be induced by hypoxemia in cardiomyopathy. The overexpression of CYP2E1 can enhance the metabolism of endogenous ketones to meet the energy demand of the heart in certain disease states, but the overexpression of CYP2E1 can also increase oxidative stress and apoptosis in the DCM heart. Knockdown or downregulation of CYP2E1 might be a therapeutic strategy to control the development of DCM after mutations of cTnT R141W or other factors, because DCM is the third most common cause of heart failure and the most frequent cause of heart transplantation.

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Section: Discussionsupporting

confidence: 61%

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confidence: 99%

Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT ^R141W Dilated Cardiomyopathy Transgenic Mice

Zhang

et al. 2012

Hypertension

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“…These data suggest not only a key role of acetaldehyde in alcoholic cardiomyopathy but also free radical formation in alcohol-and acetaldehyde-induced cardiac damage. Evidence from our laboratory and others (30,31) also indicated that the acetaldehyde-induced cellular toxicity is mediated through the ethanol-inducible isoform of cytochrome P-450, namely CYP2E1, xanthine oxidase and aldehyde oxidase. Inhibition of these enzymatic pathways significantly reduces acetaldehydeinduced lipid peroxidation, tissue and cell injury (31).…”

Section: Discussionmentioning

confidence: 61%

“…Evidence from our laboratory and others (30,31) also indicated that the acetaldehyde-induced cellular toxicity is mediated through the ethanol-inducible isoform of cytochrome P-450, namely CYP2E1, xanthine oxidase and aldehyde oxidase. Inhibition of these enzymatic pathways significantly reduces acetaldehydeinduced lipid peroxidation, tissue and cell injury (31). Metabolism of acetaldehyde through these enzymatic pathways may play an important role in oxidative stress leading to cellular pathology under alcoholism.…”

Section: Discussionmentioning

confidence: 61%

Overexpression of Aldehyde Dehydrogenase-2 (ALDH2) Transgene Prevents Acetaldehyde-induced Cell Injury in Human Umbilical Vein Endothelial Cells

Gomelsky

Duan

et al. 2004

Journal of Biological Chemistry

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109

104

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Acetaldehyde, the major ethanol metabolite that is far more toxic and reactive than ethanol, has been postulated to be responsible for alcohol-induced tissue and cell injury. This study was to examine whether facilitated acetaldehyde metabolism affects acetaldehyde-induced oxidative stress and apoptosis. Transgene-encoding human aldehyde dehydrogenase-2 (ALDH2), which converts acetaldehyde into acetate, was constructed under chicken ␤-actin promoter and transfected into human umbilical vein endothelial cells (HUVECs). Efficacy of ALDH2 transfection was verified using green fluorescent protein and ALDH2 enzymatic assay. Generation of reactive oxygen species (ROS) was measured using chloromethyl-2,7-dichlorodihydrofluorescein diacetate. Apoptosis was evaluated by 4,6-diamidino-2-phenylindoladihydrochloride fluorescence microscopy, quantitative DNA fragmentation, and caspase-3 assay. Acetaldehyde (0 -200 M) elicited ROS generation and apoptosis in HUVECs in a time-and concentration-dependent manner, associated with activation of the stress signal molecules ERK1/2 and p38 mitogen-activated protein (MAP) kinase. A close liner correlation was observed between the acetaldehyde-induced ROS generation and apoptosis. Interestingly, the acetaldehydeinduced ROS generation, apoptosis, activation of ERK1/2, and p38 MAP kinase were prevented by the ALDH2 transgene or antioxidant ␣-tocopherol. The involvement of ERK1/2 and p38 MAP kinase in acetaldehyde-induced apoptosis was confirmed by selective kinase inhibitors U0126, SB203580, and SB202190. Collectively, our data revealed that facilitation of acetaldehyde metabolism by ALDH2 transgene overexpression may prevent acetaldehyde-induced cell injury and activation of stress signals. These results indicated therapeutic potential of ALDH2 enzyme in the prevention and detoxification of acetaldehyde or alcohol-induced cell injury.Chronic alcohol consumption leads to cardiovascular complications such as endothelial dysfunction and alcoholic cardiomyopathy (1). Although several hypotheses have been speculated for alcohol-induced injury including direct/indirect toxicity of alcohol and accumulated fatty acid ethyl esters (2, 3), neither scenario has been fully validated by compelling clinical and experimental evidence. Acetaldehyde is the very first oxidized metabolic product of ethanol and is considered a candidate toxin for alcohol-induced tissue and cell injury. It is far more reactive than ethanol and may inhibit protein synthesis (4, 5). Our laboratory (6 -8) has shown that acetaldehyde interrupts cardiac excitation-contraction coupling and sarco(endo)plasmic reticulum Ca 2ϩ release function. Acetaldehyde has also been shown to form protein adducts leading to atherosclerotic vascular injury (9). Transgenic mice with cardiac overexpression of alcohol dehydrogenase (ADH) 1 displayed higher cardiac acetaldehyde levels associated with compromised heart function at whole heart and ventricular myocyte levels following alcohol intake (10 -12), suggesting that acetaldehyde may be one of t...

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“…1.1.1.1), has been implicated in mediating some of the effects of ethanol. The toxicity of acetaldehyde is manyfold greater than that of ethanol [21] and has been implicated in the development of alcohol cardiotoxity [22]. 4-Methylpyrazole (4-MP) is a specific competitive inhibitor of human ADH [23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Differential Phosphorylation of Translation Initiation Regulators 4EBP1, S6k1, and Erk 1/2 Following Inhibition of Alcohol Metabolism in Mouse Heart

Vary

Lang

2008

Cardiovasc Toxicol

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Acute alcohol intoxication leads to an inhibition of protein synthesis in heart that results in part through altered phosphorylation of protein factors controlling mRNA translation initiation. The purpose of the present set of experiments was designed to examine the effects of inhibitors of ethanol metabolism on the phosphorylation of 4E-binding protein (4EBP1) and S6k1(Thr(389)), two factors regulating mRNA translation initiation. Phosphorylation of 4E-BP1, S6k1(Thr(389)), and Erk 1/2 was reduced 2 h following IP injection of alcohol. Pretreatment with 4-methylpyrazole (4-MP), an inhibitor of alcohol dehydrogenase (ADH), did not attenuate the ethanol-induced decrease in phosphorylation of 4EBP1 and S6k1(Thr(389)). In contrast, 4-MP prevented the decrease in Erk 1/2 phosphorylation observed with acute ethanol intoxication. Pretreatment with cyanamide, an inhibitor of aldehyde dehydrogenase, did not attenuate the ethanol-induced decrease in phosphorylation S6k1(Thr(389)), but partially prevented the ethanol-induced lowering of 4EBP1 phosphorylation. The studies indicate that modulation of ethanol metabolism through inhibition of ADH or aldehyde dehydrogenase leads to preferential modulation of the phosphorylation of distinct myocardial signaling systems involved in regulating protein synthesis.

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Short‐Term Acetaldehyde Exposure Depresses Ventricular Myocyte Contraction: Role of Cytochrome P450 Oxidase, Xanthine Oxidase, and Lipid Peroxidation

Abstract: Collectively, these data provided evidence that ACA depressed cardiomyocyte mechanical function at micromolar levels, possibly through mechanisms related to CYP oxidase, xanthine oxidase, and lipid peroxidation.

Cited by 37 publications

References 36 publications

Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT ^R141W Dilated Cardiomyopathy Transgenic Mice

Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT ^R141W Dilated Cardiomyopathy Transgenic Mice

Overexpression of Aldehyde Dehydrogenase-2 (ALDH2) Transgene Prevents Acetaldehyde-induced Cell Injury in Human Umbilical Vein Endothelial Cells

Differential Phosphorylation of Translation Initiation Regulators 4EBP1, S6k1, and Erk 1/2 Following Inhibition of Alcohol Metabolism in Mouse Heart

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Short‐Term Acetaldehyde Exposure Depresses Ventricular Myocyte Contraction: Role of Cytochrome P450 Oxidase, Xanthine Oxidase, and Lipid Peroxidation

Abstract: Collectively, these data provided evidence that ACA depressed cardiomyocyte mechanical function at micromolar levels, possibly through mechanisms related to CYP oxidase, xanthine oxidase, and lipid peroxidation.

Cited by 37 publications

References 36 publications

Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT R141W Dilated Cardiomyopathy Transgenic Mice

Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT R141W Dilated Cardiomyopathy Transgenic Mice

Overexpression of Aldehyde Dehydrogenase-2 (ALDH2) Transgene Prevents Acetaldehyde-induced Cell Injury in Human Umbilical Vein Endothelial Cells

Differential Phosphorylation of Translation Initiation Regulators 4EBP1, S6k1, and Erk 1/2 Following Inhibition of Alcohol Metabolism in Mouse Heart

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Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT ^R141W Dilated Cardiomyopathy Transgenic Mice

Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT ^R141W Dilated Cardiomyopathy Transgenic Mice