Acrolein consumption exacerbates myocardial ischemic injury and blocks nitric oxide-induced PKCepsilon signaling and cardioprotection.

Department of Physiology and the Cardiovascular Research Laboratories, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Journal of Molecular and Cellular Cardiology (Impact Factor: 5.15). 07/2008; 44(6):1016-22. DOI: 10.1016/j.yjmcc.2008.03.020
Source: PubMed

ABSTRACT Aldehydes are common reactive constituents of food, water and air. Several food aldehydes are potentially carcinogenic and toxic; however, the direct effects of dietary aldehydes on cardiac ischemia-reperfusion (IR) injury are unknown. We tested the hypothesis that dietary consumption of aldehydes modulates myocardial IR injury and preconditioning. Mice were gavage-fed the alpha, beta-unsaturated aldehyde acrolein (5mg/kg) or water (vehicle) 24h prior to a 30-min coronary artery occlusion and 24-hour reperfusion. Myocardial infarct size was significantly increased in acrolein-treated mice, demonstrating that acute acrolein exposure worsens cardiac IR injury. Furthermore, late cardioprotection afforded by the nitric oxide (NO) donor diethylenetriamine/NO (DETA/NO; dose: 0.1mg/kg x 4, i.v.) was abrogated by the administration of acrolein 2h prior to DETA/NO treatment, indicating that oral acrolein impairs NO donor-induced late preconditioning. To examine potential intracellular targets of aldehydes, we investigated the impact of acrolein on mitochondrial PKCepsilon signaling in the heart. Acrolein-protein adducts were formed in a dose-dependent manner in isolated cardiac mitochondria in vitro and specific acrolein-PKCepsilon adducts were present in cardiac mitochondrial fractions following acrolein exposure in vivo, demonstrating that mitochondria are major targets of aldehyde toxicity. Furthermore, DETA/NO preconditioning induced both PKCepsilon translocation and increased mitochondrial PKCepsilon localization. Both of these responses were blocked by acrolein pretreatment, providing evidence that aldehydes disrupt cardioprotective signaling events involving PKCepsilon. Consumption of an aldehyde-rich diet could exacerbate cardiac IR injury and block NO donor-induced cardioprotection via mechanisms that disrupt PKCepsilon signaling.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Acrolein is a major reactive component of vehicle exhaust, cigarette and wood smoke. It is also present in several food substances and is generated endogenously during inflammation and lipid peroxidation. Although previous studies have shown that dietary or inhalation exposure to acrolein results in endothelial activation, platelet activation and accelerated atherogenesis, the basis for these effects is unknown. Moreover, the effects of acrolein on microRNA (miRNA) have not been studied. Using AGILENT miRNA microarray high throughput technology, we found that treatment of cultured human umbilical vein endothelial cells with acrolein led to a significant (>1.5-fold) up-regulation of 12, and down-regulation of 15, miRNAs. Among the miRNAs up-regulated were members of the let-7 family and this up-regulation was associated with decreased expression of their protein targets, β3 integrin, Cdc34 and K-Ras. Exposure to acrolein attenuated β3 integrin-dependent migration and reduced Akt phosphorylation in response to insulin. These effects of acrolein on endothelial cell migration and insulin signaling were reversed by expression of a let-7a inhibitor. Also, inhalation exposure of mice to acrolein (1ppm x 6h/day x 4 days) up-regulated let-7a and led to a decrease in insulin-stimulated Akt phosphorylation in the aorta. These results suggest that acrolein exposure has broad effects on endothelial miRNA repertoire and that attenuation of endothelial cell migration and insulin signaling by acrolein is mediated in part by the up-regulation of let-7a. This mechanism may be significant feature of vascular injury caused by inflammation, oxidized lipids, and exposure to environmental pollutants.
    Toxicological Sciences 05/2014; DOI:10.1093/toxsci/kfu087 · 4.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Acrolein, a highly reactive unsaturated aldehyde, is a ubiquitous environmental pollutant and its potential as a serious environmental health threat is beginning to be recognized. Humans are exposed to acrolein per oral (food and water), respiratory (cigarette smoke, automobile exhaust, and biocide use) and dermal routes, in addition to endogenous generation (metabolism and lipid peroxidation). Acrolein has been suggested to play a role in several disease states including spinal cord injury, multiple sclerosis, Alzheimer's disease, cardiovascular disease, diabetes mellitus, and neuro-, hepato-, and nephro-toxicity. On the cellular level, acrolein exposure has diverse toxic effects, including DNA and protein adduction, oxidative stress, mitochondrial disruption, membrane damage, endoplasmic reticulum stress, and immune dysfunction. This review addresses our current understanding of each pathogenic mechanism of acrolein toxicity, with emphasis on the known and anticipated contribution to clinical disease, and potential therapies. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail:
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Acrolein is a reactive aldehyde present in high amounts in coal, wood, paper, and tobacco smoke. It is also generated endogenously by lipid peroxidation and the oxidation of amino acids by myeloperoxidase. In animals, acrolein exposure is associated with the suppression of circulating progenitor cells and increases in thrombosis and atherogenesis. The purpose of this study was to determine whether acrolein exposure in humans is also associated with increased cardiovascular disease (CVD) risk.
    Journal of the American Heart Association 06/2014; 3(4). DOI:10.1161/JAHA.114.000934


Available from
May 26, 2014