Fe2+ Block and Permeation of CaV3.1 (α1G) T-Type Calcium Channels: Candidate Mechanism for Non–Transferrin-Mediated Fe2+ Influx

Lopin, Kyle V.; Gray, I. Patrick; Obejero‐Paz, Carlos A.; Thévenod, Frank; Jones, Stephen

doi:10.1124/mol.112.080184

Cited by 36 publications

(24 citation statements)

References 58 publications

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“…However, the mechanism of extracellular Fe 2+ entry into the cardiomyocytes through TTCC in iron overload conditions may be similar to LTCC. As expected, a previous study found that Ca V 3.1 TTCC was a significant portal for Fe 2+ entry into cells leading to an iron overload condition49. Consistent with a recent study indicated that at a high concentration of free Fe 2+ may compete with a Ca 2+ influx into the myocardium through Ca 2+ channels by both LTCC and TTCC50.…”

Section: Discussionsupporting

confidence: 88%

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

Wongjaikam

Kumfu

Khamseekaew

et al. 2017

Sci Rep

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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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Section: Discussionsupporting

confidence: 88%

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

Wongjaikam

Kumfu

Khamseekaew

et al. 2017

Sci Rep

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“…This is supported by our previous reports, which demonstrated that TTCC re-expression in the heart of thalassaemic mice could be detected by real-time PCR and microarray (Kumfu et al , 2012a. Moreover, Lopin et al (2012) demonstrated that Fe 2+ inhibited Ca 2+ currents and that Fe 2+ could enter cardiomyocytes through the TTCC in iron-overloaded conditions. These findings suggest that the TTCC could play an important role in cardiac iron uptake in iron-overloaded conditions.…”

Section: Discussionsupporting

confidence: 86%

“…It has been shown that L-type calcium channels (LTCCs), T-type calcium channels (TTCCs) and divalent metal transporter1 (DMT1) play a role in iron uptake into the heart in a iron-overloaded conditions (Tsushima et al 1999;Crowe & Bartfay, 2002;Oudit et al 2003;Kumfu et al 2011Kumfu et al , 2012aLopin et al 2012;Musumeci et al 2013). Once iron is taken up into the cells, it is either stored as ferritin or transferred across the cell membrane into the blood circulation by the iron exporter ferroportin (Gunshin et al 1997;Fleming et al 1998;Abboud & Haile, 2000;Donovan et al 2000).…”

Section: Introductionmentioning

confidence: 99%

“…Several studies have shown the beneficial effects of iron chelators, a dual TTCC and LTCC blocker and an LTCC blocker on cardiac iron accumulation and cardiac function in iron-overloaded conditions (Tsushima et al 1999;Crowe & Bartfay, 2002;Oudit et al 2003;Kumfu et al 2011Kumfu et al , 2012aLopin et al 2012;Musumeci et al 2013). However, none of these studies has determined the comparative beneficial effects between the three commercial iron chelators, a dual TTCC and LTCC blocker and an LTCC blocker on cardiac iron accumulation, cardiac function, cardiac mitochondrial function, cardiac iron transporters (Zip14, DMT1, TTCC and LTCC), iron exporter (ferroportin), iron regulatory hormone (hepcidin) and apoptotic protein expression, in normal and thalassaemic mice in iron-overloaded conditions.…”

Section: Introductionmentioning

confidence: 99%

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Dual T‐type and L‐type calcium channel blocker exerts beneficial effects in attenuating cardiovascular dysfunction in iron‐overloaded thalassaemic mice

Kumfu

Chattipakorn

Fucharoen

et al. 2016

Experimental Physiology

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New Findings r What is the central question of this study? Head-to-head comparison of the therapeutic efficacy among commercial iron chelators and a dual T-(TTCC) and L-type calcium channel (LTCC) blocker on cardiac function, mitochondrial function and the protein expression of cardiac iron transporters in thalassaemic mice in iron-overloaded conditions has not been assessed. r What is the main finding and its importance?The dual TTCC and LTCC blocker efonidipine could provide broad beneficial effects in the heart, liver, plasma and mitochondria in both wild-type and thalassaemic mice in iron-overloaded conditions. Its beneficial effects are of the same degree as the three commercial iron chelators currently used clinically. It is possible that efonidipine could be an alternative choice in patients unable to take iron chelators for the treatment of iron-overload conditions. Iron chelation therapy is a standard treatment in thalassaemia patients; however, its poor cardioprotective efficacy and serious side-effects are a cause for concern. Previous studies have shown that treatment with L-type calcium channel (LTCC) blockers or dual T-type calcium channel (TTCC) and LTCC blockers decreases cardiac iron and improves cardiac dysfunction in an iron-overloaded rodent model. Currently, the head-to-head comparison of therapeutic efficacy among commercial iron chelators, a dual TTCC and LTCC blocker and an LTCC blocker on cardiac function, mitochondrial function and the protein expression of cardiac iron transporters in thalassaemic mice in an iron-overloaded state has never been investigated. An iron-overloaded state was induced in β-thalassaemic and wild-type mice. Cardiac iron overload was induced to a greater extent than in a previous study by feeding the mice with an iron-enriched diet for 4 months. Then, an LTCC blocker (amlodipine) or a dual TTCC and LTCC blocker (efonidipine) or one of the commercial iron chelators (deferoxamine, deferasirox or deferiprone) was administered for 1 month with continuous iron feeding. All treatments reduced cardiac iron deposition and improved mitochondrial and cardiac dysfunction in both types of mice. Only efonidipine and the iron chelators reduced liver iron accumulation, liver malondialdehyde and plasma malondialdehyde in these mice. Although all pharmacological interventions reduced cardiac iron deposition, they did not alter the protein expression levels of

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“…Chattipakorn, 2012; Kumfu et al, 2011;Lopin, Gray, Obejero-Paz, Thevenod, & Jones, 2012) and L-type calcium channels (LTCC) (Crowe & Bartfay, 2002;Fernandes et al, 2013;Oudit et al, 2003). Studies regarding Lcn2-mediated iron accumulation in iron-overloaded cardiomyocytes that are concurrently treated with iron-chelating therapeutic agents and antagonists of the aforementioned ironimporting systems are also lacking.…”

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confidence: 99%

Roles of lipocalin 2 and adiponectin in iron overload cardiomyopathy

Siri‐Angkul

Chattipakorn

2018

Journal Cellular Physiology

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Thalassemia is among the most common genetic diseases worldwide. Ineffective erythropoiesis, chronic hemolysis, and regular blood transfusion in thalassemia patients lead to increased iron burden. Iron overload cardiomyopathy is the most severe co-morbidity and most common cause of mortality in thalassemia patients. Although its associated mechanisms are still not completely understood, cellular iron mishandling, chronic inflammation, and oxidative stress appear to be the key processes involved. In order to acquire a more comprehensive insight of the impact of cardiac iron overload, these alterations need to be intensively investigated. This comprehensive mini-review focuses on two emergent molecules which have been shown to potentially play significant roles in iron overload cardiomyopathy. These two molecules are an iron-transporting protein, lipocalin 2, and an anti-inflammatory adipokine, adiponectin. Reports from in vitro and in vivo studies are comprehensively summarized. Clinical studies examining the roles of these molecules in thalassemia patients are also presented and discussed.

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Fe²⁺ Block and Permeation of Ca_V3.1 (α1G) T-Type Calcium Channels: Candidate Mechanism for Non–Transferrin-Mediated Fe²⁺ Influx

Cited by 36 publications

References 58 publications

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

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

Dual T‐type and L‐type calcium channel blocker exerts beneficial effects in attenuating cardiovascular dysfunction in iron‐overloaded thalassaemic mice

Roles of lipocalin 2 and adiponectin in iron overload cardiomyopathy

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