Abstract
PurposeHyperhomocysteinemia is an independent risk factor for cardiovascular diseases and also promotes neuronal death in various neurodegenerative diseases. There is evidence that iron can mediate homocysteine (Hcy) toxicity. Thus, the aim of this study was to investigate the effect of Hcy on iron metabolism in HUVEC and SH-SY5Y cells.MethodsHUVEC and SH-SY5Y cells were treated with 3 mM Hcy for a defined time.ResultsWe demonstrate that Hcy induced the upregulation of ferritins type L and H in HUVEC cells in a time-dependent manner and had no effect on the ferritins in SH-SY5Y cells. The change in ferritin expression was preceded by a significant decrease in the cellular level of the active form of Akt kinase in HUVEC but not in SH-SY5Y cells. An increase in ferritin L and H protein levels was observed in the Akt1, Akt2, Akt3 siRNA transfected cells, while in the cells transfected with FOXO3a siRNA, a decrease in both ferritins levels was noticed. Moreover, in the HUVEC cells treated with Hcy for 6 days, the active form of kinase Akt returned to the control level and it was accompanied by a drop in ferritin L and H protein levels. Cytotoxicity of hydrogen peroxide significantly increased in HUVEC cells pre-treated with Hcy for 24 h.ConclusionsThese data indicate that Hcy induces an increase in cellular ferritin level, and the process is mediated by alterations in Akt-FOXO3a signaling pathway.
Highlights
Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases, such as ischemic heart disease, stroke, peripheral vascular disease or atherosclerosis [1]
We show for the first time that homocysteine treatment leads to changes in iron metabolism via impairment of Akt serine/threonine kinase signaling
We demonstrate that 3 mM Hcy-induced changes in iron metabolism in HUVEC cells are manifested by increased ferritin L and H protein levels, and increased sensitivity to hydrogen peroxide
Summary
Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases, such as ischemic heart disease, stroke, peripheral vascular disease or atherosclerosis [1]. It was demonstrated that Hcy affected multiple signaling pathways, including extracellular signal-regulated kinase (ERK), Dyrk1A serine/threonine kinase involved in diverse cellular processes, PI3K/Akt pathway, stress-activated protein kinase, and others. Hyperhomocysteinemia in rats was shown to be associated with the inactivation of PI3K/Akt signaling pathway, and the deleterious effects of Hcy were reversed by Akt kinase activators [4,5,6]. These data suggest that Akt inactivation plays an essential
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