4-Hydroxy-2-nonenal protects against cardiac ischemia-reperfusion injury via the Nrf2-dependent pathway

Yan Zhang, Motoaki Sano, Ken Shinmura, Kayoko Tamaki, Yoshinori Katsumata, Tomohiro Matsuhashi, Shintaro Morizane, Hideyuki Ito, Takako Hishiki, Jin Endo, Heping Zhou, Shinsuke Yuasa, Ruri Kaneda, Makoto Suematsu, Keiichi Fukuda

Research output: Contribution to journalArticlepeer-review

122 Citations (Scopus)


Reactive oxygen species (ROS) attack polyunsaturated fatty acids of the membrane and trigger lipid peroxidation, which results in the generation of α,β-unsaturated aldehydes, such as 4-hydroxy-2-nonenal (4-HNE). There is compelling evidence that high concentrations of aldehydes are responsible for much of the damage elicited by cardiac ischemia-reperfusion injury, while sublethal concentrations of aldehydes stimulate stress resistance pathways, to achieve cardioprotection. We investigated the mechanism of cardioprotection mediated by 4-HNE. For cultured cardiomyocytes, 4-HNE was cytotoxic at higher concentrations (≥20μM) but had no appreciable cytotoxicity at lower concentrations. Notably, a sublethal concentration (5μM) of 4-HNE primed cardiomyocytes to become resistant to cytotoxic concentrations of 4-HNE. 4-HNE induced nuclear translocation of transcription factor NF-E2-related factor 2 (Nrf2), and enhanced the expression of γ-glutamylcysteine ligase (GCL) and the core subunit of the Xc- high-affinity cystine transporter (xCT), thereby increasing 1.45-fold the intracellular GSH levels. Cardiomyocytes treated with either Nrf2-specific siRNA or the GCL inhibitor l-buthionine sulfoximine (BSO) were less tolerant to 4-HNE. Moreover, the cardioprotective effect of 4-HNE pretreatment against subsequent glucose-free anoxia followed by reoxygenation was completely abolished in these cells. Intravenous administration of 4-HNE (4mg/kg) activated Nrf2 in the heart and increased the intramyocardial GSH content, and consequently improved the functional recovery of the left ventricle following ischemia-reperfusion in Langendorff-perfused hearts. This cardioprotective effect of 4-HNE was not observed for Nrf2-knockout mice. In summary, 4-HNE activates Nrf2-mediated gene expression and stimulates GSH biosynthesis, thereby conferring on cardiomyocytes protection against ischemia-reperfusion injury.

Original languageEnglish
Pages (from-to)576-586
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Issue number4
Publication statusPublished - 2010 Oct


  • 4-Hydroxy-2-nonenal
  • Glutathione
  • Hormesis
  • Ischemia-reperfusion injury
  • Nrf2

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine


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