4-Hydroxy-2-nonenal Induces Calcium Overload via the Generation of Reactive Oxygen Species in Isolated Rat Cardiac Myocytes

Kazufumi Nakamura, Daiji Miura, Kengo Fukushima Kusano, Yoshihisa Fujimoto, Wakako Sumita-Yoshikawa, Soichiro Fuke, Nobuhiro Nishii, Satoshi Nagase, Yoshiki Hata, Hiroshi Morita, Hiromi Matsubara, Tohru Ohe, Hiroshi Ito

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Background: It has been reported that that the amount of 4-hydroxy-2-nonenal (HNE), which is a major lipid peroxidation product and a cytotoxic aldehyde, is increased in the human failing myocardium. This study was designed to determine whether HNE has a pro-oxidant effect in cardiac myocytes and whether HNE causes Ca2+ overload. Methods and Results: Exposure to HNE for 10 minutes in the presence of ferric nitrilotriacetate induced the production of hydroxyl radical (·OH) in the rat myocardium as assessed by electron spin resonance spectroscopy, and HNE induced the generation of reactive oxygen species (ROS) in a dose-dependent manner as assessed by 2′, 7′-dichlorofluorescein diacetate fluorescence. HNE increased intracellular Ca2+ concentration ([Ca2+]i) as assessed by fura-2 ratio in a dose- and time-dependent manner. After 20 minutes of HNE (400 μmol/L) exposure, hypercontracture was induced in 67% of the cells. Catalase, an antioxidative enzyme that can decompose hydrogen peroxide (H2O2), significantly attenuated the increase in [Ca2+]i and completely inhibited hypercontracture. Carvedilol, a β-blocker with potent antioxidant activity, also significantly attenuated the increase in [Ca2+]i and completely inhibited hypercontracture, but propranolol had no effect on either [Ca2+]i increase or hypercontracture. Conclusions: HNE induces the formation of ROS, especially H2O2 and ·OH, in cardiomyocytes and subsequently ROS cause intracellular Ca2+ overload. HNE formation may play an important role as a mediator of oxidative stress in heart failure.

Original languageEnglish
Pages (from-to)709-716
Number of pages8
JournalJournal of Cardiac Failure
Issue number8
Publication statusPublished - Oct 1 2009



  • Reactive oxygen species
  • calcium overload
  • heart failure

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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