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NON-TRANSFERRIN-BOUND IRON (NTBI) AND APOTRANSFERRIN STIMULATE THE EXPRESSION OF L-TYPE VOLTAGE-GATED CALCIUM CHANNELS OF CARDIOMYOCYTES

Wiener, E; Chennell, G; Garbowski, M; Porter, J; (2013) NON-TRANSFERRIN-BOUND IRON (NTBI) AND APOTRANSFERRIN STIMULATE THE EXPRESSION OF L-TYPE VOLTAGE-GATED CALCIUM CHANNELS OF CARDIOMYOCYTES. In: (Proceedings) BioIron 2013. (pp. E75-E75).

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Abstract

Introduction: In iron overload, the iron - binding capacity of transferrin is near saturation: NTBI species appear (0.4 - 10 μM) while apotransferrin is g rossly reduced or absent. NTBI is taken up by the heart, liver and endocrine tissues inflicting damage to these organs. In a mouse model of iron - overload, the uptake of ferrous iron by the myocardium was related to L - type voltage - gated calcium channels (1) while recently, Kumfu et al showed that T - type calcium channels are involved in the cardiac pathology of β - thalassaemic mice (2). Additionally, iron loading of HuH7 liver cells causes modulation of membrane T - and L - type calcium channels (3). We have inve stigated the effect of NTBI and apotransferrin on the expression of L - and T - type calcium channels of HL - 1 cardiomyocytes. Methods : Cardiomyocytes expressing both L - and T - type calcium channels (4) were cultured (5) and plated out on chamber slides (4 cham bers/slide, 2x105/chamber). Next day they were re - incubated in Claycomb medium containing different concentrations of ferric ammonium citrate (FAC) or apotransferrin. After 24h they were washed, fixed in paraformaldehyde, permeabilised in triton X - 100, inc ubated overnight with rabbit antibodies against α 1 subunit D (L - type) or α 1 subunit H (T - type) and subsequently stained with an FITC - labelled anti - rabbit Ig antibody and submitted to quantitative confocal microscopy. Fluorescence analysis was performed u sing the Volocity program and the results expressed as object measurements (total cellular α 1 subunit) and line profiles (α 1 subunit intracellular distribution). Results : Treatment of HL - 1 for 24h with 2uM FAC consistently caused an almost two - fold rise in α1 subunit D (p<0.05) while with the higher FAC concentrations (20, 200 μM), stimulation was less pronounced. Line profiles revealed no change in the intracellular distribution. With the subnormal apotransferrin concentration of 10μM there was an almost two fold increase in α 1 subunit D. Line profiles revealed redistribution of this subunit from the cell centre to the periphery. By contrast, under any of these conditions, the expression of α1 subunit H remained unchanged. Discussion : The stimulated expr ession by HL - 1 cells of α1 subunit D at low concentrations of FAC and apotransferrin suggests that in iron overload, these factors bring about a rise in cardiac L - type calcium channels that mediate influx of iron into the heart. The angiotensin II - induced cardiac expression of Ltype α1C subunit is mediated via a protein kinase C - , reactive oxygen - mediated species - and CREB - dependent pathway (6). A similar mechanism might underlie the induction of the L - type α 1D subunit by NTBI/apotransferrin in the present system. References 1. Tsushima RA, Wickenden AD, Bauchard RA, et al. (1999) Circ Res 84:1302 2. Kumfu S, Chattiparkorn S, Chinda K, et al. (2012) Europ J Haematologyl 88:535 3. Wiener E, Rafique R, Pizzey A, Adejumo T, Chennell G, Porter JB. (2011) Blood 118:1038 4 Xia M, Salata JJ, Figueroa, DJ, Lawlor AM, et al, (2004) J Mol Cell Cardiol 36:111 5 Claycomb W, Lansa NA, Stanworth DS et al (1995) PNAS 95:2979 6 Tsai C - T, Ling Wang D, Chen, J - J, Hwang J - J et al (2007) Circ Res 36:100

Type: Proceedings paper
Title: NON-TRANSFERRIN-BOUND IRON (NTBI) AND APOTRANSFERRIN STIMULATE THE EXPRESSION OF L-TYPE VOLTAGE-GATED CALCIUM CHANNELS OF CARDIOMYOCYTES
Event: BioIron 2013
Location: UCL, London
DOI: 10.1002/ajh.23453
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: http://discovery.ucl.ac.uk/id/eprint/1431421
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