Combined Iron Chelator and Antioxidant Exerted Greater Efficacy on Cardioprotection Than Monotherapy in Iron-Overloaded Rats.

Suwakon Wongjaikam,Suthat Fucharoen,Somdet Srichairatanakool,Nipon Chattipakorn,Jirapas Sripetchwandee,Siriporn C Chattipakorn,Sirinart Kumfu,Juthamas Khamseekaew,Michael Bader

doi:10.1371/journal.pone.0159414

Suwakon Wongjaikam, Suthat Fucharoen + Show 7 more

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https://doi.org/10.1371/journal.pone.0159414

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Journal: PloS one	Publication Date: Jul 18, 2016
Citations: 47	License type: CC BY 4.0

Affiliation: Chiang Mai University, Mahidol University

Abstract

BackgroundIron chelators are used to treat iron overload cardiomyopathy patients. However, a direct comparison of the benefits of three common iron chelators (deferoxamine (DFO), deferiprone (DFP) and deferasirox (DFX)) or an antioxidant (N-acetyl cysteine (NAC)) with a combined DFP and NAC treatments on left ventricular (LV) function with iron overload has not been investigated.Methods and FindingsMale Wistar rats were fed with either a normal diet or a high iron diet (HFe group) for 4 months. After 2 months, the HFe-fed rats were divided into 6 groups to receive either: a vehicle, DFO (25 mg/kg/day), DFP (75 mg/kg/day), DFX (20 mg/kg/day), NAC (100 mg/kg/day) or the combined DFP and NAC for 2 months. Our results demonstrated that HFe rats had increased plasma non-transferrin bound iron (NTBI), malondialdehyde (MDA), cardiac iron and MDA levels and cardiac mitochondrial dysfunction, leading to LV dysfunction. Although DFO, DFP, DFX or NAC improved these parameters, leading to improved LV function, the combined DFP and NAC therapy caused greater improvement, leading to more extensively improved LV function.ConclusionsThe combined DFP and NAC treatment had greater efficacy than monotherapy in cardioprotection through the reduction of cardiac iron deposition and improved cardiac mitochondrial function in iron-overloaded rats.

Highlights

The iron overload condition is often seen in transfusion dependent thalassemia (TDT) patients due to repeated blood transfusions, and in hereditary hemochromatosis patients due to increased dietary iron absorption into the duodenal enterocytes [1,2,3,4,5]
Our results demonstrated that HFe rats had increased plasma non-transferrin bound iron (NTBI), malondialdehyde (MDA), cardiac iron and MDA levels and cardiac mitochondrial dysfunction, leading to left ventricular (LV) dysfunction
Plasma NTBI was significantly increased in the HFe-fed rats, while levels of plasma NTBI could not be detected in the control group (Fig 2A), indicating that an iron overload condition occurred in the HFe-fed rats

Summary

Introduction

The iron overload condition is often seen in transfusion dependent thalassemia (TDT) patients due to repeated blood transfusions, and in hereditary hemochromatosis patients due to increased dietary iron absorption into the duodenal enterocytes [1,2,3,4,5]. Cardiac iron toxicity occurs when there is too much labile iron in the cell and this free iron reacts with superoxide (O2-) and hydrogen peroxide (H2O2) via Haber-Weiss and Fenton’s reactions to produce the highly toxic hydroxyl radical (OH). The production of this free radical leads to an increase in the levels of reactive oxygen species (ROS) [13, 14] and cardiac oxidative stress, leading to damages of cardiac cells which results in cardiac dysfunction and heart failure [14, 15]. A direct comparison of the benefits of three common iron chelators (deferoxamine (DFO), deferiprone (DFP) and deferasirox (DFX)) or an antioxidant (N-acetyl cysteine (NAC)) with a combined DFP and NAC treatments on left ventricular (LV) function with iron overload has not been investigated

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