Downregulation of ferritin heavy chain increases labile iron pool, oxidative stress and cell death in cardiomyocytes

Shigemiki Omiya, Shungo Hikoso, Yukiko Imanishi, Atsuhiro Saito, Osamu Yamaguchi, Toshihiro Takeda, Isamu Mizote, Takafumi Oka, Manabu Taneike, Yuko Nakano, Yasushi Matsumura, Kazuhiko Nishida, Yoshiki Sawa, Masatsugu Hori, Kinya Otsu

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50 Citations (Scopus)


Ferritin heavy chain (FHC) protein was significantly reduced in murine failing hearts following left coronary ligation or thoracic transverse aortic constriction. The mRNA expression of FHC was not significantly altered in failing hearts, compared to that in control sham-operated hearts. Prussian blue staining revealed spotty iron depositions in myocardial infarct failing hearts. Oxidative stress was enhanced in the myocardial infarct failing hearts, as evidenced by increases in 4-hydroxy-2-nonenal and 8-hydroxy-2'-deoxyguanosine immunoreactivity. To clarify the functional significance of FHC downregulation in hearts, we infected rat neonatal cardiomyocytes with adenoviral vector expressing short hairpin RNA targeted to FHC (Ad-FHC-RNAi). The downregulation of FHC induced a reduction in the viability of cardiomyocytes. The relative number of iron deposition-. 4-hydroxy-2-nonenal- or 8-hydroxy-2'-deoxyguanosine-positive cardiomyocytes was significantly higher in Ad-FHC-RNAi-infected cardiomyocytes than in control vector-infected cardiomyocytes. Treatment of Ad-FHC-RNAi-infected cardiomyocytes with desferrioxamine, an iron chelator, significantly reduced the number of iron. 4-hydroxy-2-nonenal or 8-hydroxy-2'-deoxyguanosine-positive cells, and increased viability. In addition, treatment with N-acetyl cysteine, an antioxidant, significantly reduced the number of 4-hydroxy-2-nonenal- or 8-hydroxy-2'-deoxyguanosine-positive cells. Reduced viability in Ad-FHC-RNAi-infected cardiomyocytes was significantly improved with N-acetyl cysteine treatment. These findings indicate that excessive free iron and the resultant enhanced oxidative stress caused by downregulation of FHC lead to cardiomyocyte death. The decrease in FHC expression in failing hearts may play an important role in the pathogenesis of heart failure. (C) 2008 Elsevier Inc. All rights reserved.

Original languageEnglish
Pages (from-to)59-66
Number of pages8
JournalJournal of Molecular and Cellular Cardiology
Issue number1
Publication statusPublished - Jan 2009


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