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

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 α, β-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 × 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 PKCε signaling in the heart. Acrolein-protein adducts were formed in a dose-dependent manner in isolated cardiac mitochondria in vitro and specific acrolein-PKCε 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 PKCε translocation and increased mitochondrial PKCε localization. Both of these responses were blocked by acrolein pretreatment, providing evidence that aldehydes disrupt cardioprotective signaling events involving PKCε. Consumption of an aldehyde-rich diet could exacerbate cardiac IR injury and block NO donor-induced cardioprotection via mechanisms that disrupt PKCε signaling.