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

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.

Restoring the impaired cardiac calcium homeostasis and cardiac function in iron overload rats by the combined deferiprone and N-acetyl cysteine

“…Although iron overload did not alter the level of cardiac LTCC protein in this study, LTCC activity might be altered in the hearts of the HFe-fed rats and this needs to be investigated further. In addition, our previous study found that rats with iron-overload for 4 months had both increased systemic iron (plasma NTBI) and cardiac iron concentrations42 which were consistent with an increase in TTCC protein expression in this study. Plasma NTBI levels were used to determine an iron status in iron-overloaded patients including hereditary hemochromatosis, β-thalassemia, myelodysplastic syndrome and sickle cell disease51.…”

“…Finally, %LVEF was significantly decreased in the HFe-fed rats leading to LV dysfunction in our study. In addition, our previous study and others demonstrated that an increase in cardiac iron store led to increased cardiac oxidative stress which caused increased mitochondrial dysfunction, resulting in cardiac dysfunction and iron overload cardiomyopathy742. In consistency, a previous study found that iron overload-evoked production of cardiac oxidative stress contributed to damage to mitochondrial DNA, reduced complex I (NADH dehydrogenase) and complex IV (cytochrome c oxidase) activities, and decreased cardiac mitochondrial respiration, leading to mitochondrial and cardiac dysfunctions in iron-overloaded mice56.…”

“…Iron-catalyzed Haber-Weiss and Fenton’s reactions led to increased ROS production in iron overloaded rat’s plasma and heart tissue42. Iron overloading mediated oxidative stress and altered cardiac excitation-contraction coupling which contributed to decreased systolic and increased diastolic Ca 2+ levels, which resulted in inhibited systolic and diastolic functions; a characteristic of iron overload cardiomyopathy248.…”

“…In addition, growing evidence indicates that N-acetyl cysteine (NAC) has an iron chelating property38, and is a potent antioxidant which is used to treat children with β-thalassemia39. Moreover, our recent study also found that combined DFP plus NAC had synergistic beneficial effects in restoring function to the brain4041 and heart42 in iron-overloaded rats. However, the effects of combining an oral iron chelator DFP and an antioxidant NAC on cardiac [Ca 2+ ]i homeostasis as well as the impact of this treatment on calcium cycling and iron regulatory proteins in iron-overloaded rats have never been investigated.…”

Bisphenol A aggravates renal ischemia–reperfusion injury by disrupting mitochondrial homeostasis and N‐acetylcysteine mitigates the injurious outcomes

“…Importantly, the protective role of NAC in BPA toxicity has recently been revealed in a rat model of BPA‐induced neurotoxicity . Furthermore, there are increasing research data supporting the advantage of NAC as an effective mitochondrial protective agent apart from its antioxidant potential . As oxidative stress and mitochondrial alterations are the hallmark of the pathogenesis in both AKI and BPA, we therefore examined the possible protection by NAC against any impacts of BPA in the kidneys after ischemia–reperfusion episode.…”