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

Suwakon Wongjaikam,Juthamas Khamseekaew,Nipon Chattipakorn,Sirinart Kumfu,Siriporn C Chattipakorn

doi:10.1038/srep44460

Suwakon Wongjaikam, Juthamas Khamseekaew + Show 3 more

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https://doi.org/10.1038/srep44460

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Journal: Scientific Reports	Publication Date: Mar 13, 2017
Citations: 38	License type: open-access

Affiliation: Chiang Mai University

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Intracellular calcium [Ca2+]i dysregulation plays an important role in the pathophysiology of iron overload cardiomyopathy. Although either iron chelators or antioxidants provide cardioprotection, a comparison of the efficacy of deferoxamine (DFO), deferiprone (DFP), deferasirox (DFX), N-acetyl cysteine (NAC) or a combination of DFP plus NAC on cardiac [Ca2+]i homeostasis in chronic iron overload has never been investigated. Male Wistar rats were fed with either a normal diet or a high iron (HFe) diet for 4 months. At 2 months, HFe rats were divided into 6 groups and treated with either a vehicle, DFO (25 mg/kg/day), DFP (75 mg/kg/day), DFX (20 mg/kg/day), NAC (100 mg/kg/day), or combined DFP plus NAC. At 4 months, the number of cardiac T-type calcium channels was increased, whereas cardiac sarcoplasmic-endoplasmic reticulum Ca2+ ATPase (SERCA) was decreased, leading to cardiac iron overload and impaired cardiac [Ca2+]i homeostasis. All pharmacological interventions restored SERCA levels. Although DFO, DFP, DFX or NAC alone shared similar efficacy in improving cardiac [Ca2+]i homeostasis, only DFP + NAC restored cardiac [Ca2+]i homeostasis, leading to restoring left ventricular function in the HFe-fed rats. Thus, the combined DFP + NAC was more effective than any monotherapy in restoring cardiac [Ca2+]i homeostasis, leading to restored myocardial contractility in iron-overloaded rats.

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Exist and contribute to cardiac electrical activity during the early embryonic state[20] and disappear shortly after birth so they cannot be found in adult ventricular cardiomyocytes under physiological conditions[21,22]
Plasma Non-transferrin bound iron (NTBI) level was significantly increased in the HFeV rats when compared with the NDV rats, indicating that an iron overload condition occurred in the HFe-fed rats (Supplementary Table 1)
It is significant that our results show that combined DFP plus N-acetyl cysteine (NAC) exerted synergistically beneficial effects on cardiac [Ca2+]i transients, and the combination therapy was more effective than monotherapy in iron-overloaded rats

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Introduction

Exist and contribute to cardiac electrical activity during the early embryonic state[20] and disappear shortly after birth so they cannot be found in adult ventricular cardiomyocytes under physiological conditions[21,22]. A head to head comparison of the comparative therapeutic effects between DFO, DFP or DFX on cardiac [Ca2+]i homeostasis as well as calcium cycling and iron regulatory proteins in iron-overloaded rats has never been investigated. The effects of combining an oral iron chelator DFP and an antioxidant NAC on cardiac [Ca2+]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. The aim of this study was to investigate the hypothesis that DFO, DFP, DFX or NAC alone can improve cardiac [Ca2+]i homeostasis and left ventricular (LV) function in iron-overloaded rats, as well as whether the combined DFP plus NAC treatment can synergistically provide beneficial effects for these conditions

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