Abstract
BackgroundIron is essential not only for erythropoisis but also for several bioenergetics’ processes in myocardium. Hepcidin is a well-known regulator of iron homeostasis. Recently, researchers identified low hepcidin was independently associated with increased 3-year mortality among systolic heart failure patients. In addition, our previous in vivo study revealed that the left ventricular mass index increased in chronic kidney disease patients with lower serum hepcidin. We hypothesize that hepcidin interacts with the apoptotic pathway of cardiomyocytes during oxidative stress conditions.MethodsTo test this hypothesis, human cardiomyocytes were cultured and treated with ferrous iron. The possible underlying signaling pathways of cardiotoxicity were examined following knockdown studies using siRNAs of hepcidin (siRNA1 was used as a negative control and siRNA2 was used to silence hepcidin).ResultsWe found that ferrous iron induces apoptosis in human cardiomyocytes in a dose-dependent manner. This iron-induced apoptosis was linked to enhanced caspase 8, reduced Bcl-2, Bcl-xL, phosphorylated Akt and GATA-4. Hepcidin levels increased in human cardiomyocytes pretreated with ferrous iron and returned to non-iron treated levels following siRNA2 transfection. In iron pretreated cardiomyocytes, the siRNA2 transfection further increased caspase 8 expression and decreased the expression of GATA-4, Bcl-2, Bcl-xL and phosphorylated Akt than iron pretreatment alone, but caspase 9 levels remained unchanged.ConclusionsOur findings suggest that hepcidin can rescue human cardiomyocytes from iron-induced apoptosis through the regulation of GATA-4/Bcl-2 and the extrinsic apoptotic pathway.
Highlights
Iron is essential for erythropoiesis and for several bioenergetic processes in the myocardium [1]
Ferrous iron induces cell death in human cardiomyocytes Cardiac cell death is believed to be a major contributor in the development and progression of myocardial dysfunction [31]
The BrdU assay revealed that ferrous iron induced human cardiomyocyte cell death in a dose-dependent manner (Figure 1)
Summary
Iron is essential for erythropoiesis and for several bioenergetic processes in the myocardium [1]. Excess extracellular iron in heart muscle is thought to induce the formation of reactive oxygen species (ROS), such as superoxide and hydroxyl radicals via the Haber Weiss and Fenton reactions. The overproduction of these ROS, in turn, increases the susceptibility to cardiac injury. The pivotal role of hepcidin in iron homeostasis was established in transgenic mouse models and in human diseases that result because of either its excess or deficiency [6,7]. Researchers identified low hepcidin was independently associated with increased 3-year mortality among systolic heart failure patients. We hypothesize that hepcidin interacts with the apoptotic pathway of cardiomyocytes during oxidative stress conditions
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