Downregulation of ferritin heavy chain increases labile iron pool, oxidative stress and cell death in cardiomyocytes.
Downregulation of ferritin heavy chain increases labile iron pool, oxidative stress and cell death in cardiomyocytes.
复制标题
DOI：
10.1016/j.yjmcc.2008.09.714
复制
发表时间：
2008-10
影响因子：
5
通讯作者：
S. Omiya;S. Hikoso;Y. Imanishi;Atsuhiro Saito;O. Yamaguchi;Toshihiro Takeda;Isamu Mizote;T. Oka;Manabu Taneike;Yuko Nakano;Y. Matsumura;K. Nishida;Y. Sawa;M. Hori;K. Otsu
中科院分区：
文献类型：
--
作者：
S. Omiya;S. Hikoso;Y. Imanishi;Atsuhiro Saito;O. Yamaguchi;Toshihiro Takeda;Isamu Mizote;T. Oka;Manabu Taneike;Yuko Nakano;Y. Matsumura;K. Nishida;Y. Sawa;M. Hori;K. Otsu
铁蛋白重链（FHC）蛋白显着减少小鼠衰竭心脏左冠状动脉结扎或胸主动脉缩窄。与假手术对照组相比，衰竭心脏FHC的mRNA表达无明显变化。普鲁士蓝染色显示，在心肌梗死衰竭的心脏斑点状铁沉积。心肌梗死衰竭心脏的氧化应激增强，表现为4-羟基-2-壬烯醛和8-羟基-2 ′-脱氧鸟苷免疫反应性增加。为了阐明FHC下调在心脏中的功能意义，我们用表达靶向FHC的短发夹RNA的腺病毒载体（Ad-FHC-RNAi）感染新生大鼠心肌细胞。FHC的下调导致心肌细胞活力的降低。在Ad-FHC-RNAi感染的心肌细胞中，铁沉积、4-羟基-2-壬烯醛或8-羟基-2 ′-脱氧鸟苷阳性的心肌细胞的相对数量显著高于对照载体感染的心肌细胞。用去铁胺（一种铁螯合剂）处理Ad-FHC-RNAi感染的心肌细胞，显著减少了铁、4-羟基-2-壬烯醛或8-羟基-2 ′-脱氧鸟苷阳性细胞的数量，并增加了存活率。此外，用抗氧化剂N-乙酰半胱氨酸处理显著减少了4-羟基-2-壬烯醛或8-羟基-2 ′-脱氧鸟苷阳性细胞的数量。用N-乙酰半胱氨酸处理显著改善了Ad-FHC-RNAi感染的心肌细胞中降低的存活率。这些发现表明，过量的游离铁和由此产生的FHC下调引起的氧化应激增强导致心肌细胞死亡。FHC在心力衰竭心脏中表达的减少可能在心力衰竭的发病机制中起重要作用。
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.