Journal of Molecular Medicine

, Volume 84, Issue 5, pp 349–364 | Cite as

Role of L-type Ca2+ channels in iron transport and iron-overload cardiomyopathy

  • Gavin Y. Oudit
  • Maria G. Trivieri
  • Neelam Khaper
  • Peter P. Liu
  • Peter H. Backx
Review

Abstract

Excessive body iron or iron overload occurs under conditions such as primary (hereditary) hemochromatosis and secondary iron overload (hemosiderosis), which are reaching epidemic levels worldwide. Primary hemochromatosis is the most common genetic disorder with an allele frequency greater than 10% in individuals of European ancestry, while hemosiderosis is less common but associated with a much higher morbidity and mortality. Iron overload leads to iron deposition in many tissues especially the liver, brain, heart and endocrine tissues. Elevated cardiac iron leads to diastolic dysfunction, arrhythmias and dilated cardiomyopathy, and is the primary determinant of survival in patients with secondary iron overload as well as a leading cause of morbidity and mortality in primary hemochromatosis patients. In addition, iron-induced cardiac injury plays a role in acute iron toxicosis (iron poisoning), myocardial ischemia–reperfusion injury, Friedreich ataxia and neurodegenerative diseases. Patients with iron overload also routinely suffer from a range of endocrinopathies, including diabetes mellitus and anterior pituitary dysfunction. Despite clear connections between elevated iron and clinical disease, iron transport remains poorly understood. While low-capacity divalent metal and transferrin-bound transporters are critical under normal physiological conditions, L-type Ca2+ channels (LTCC) are high-capacity pathways of ferrous iron (Fe2+) uptake into cardiomyocytes especially under iron overload conditions. Fe2+ uptake through L-type Ca2+ channels may also be crucial in other excitable cells such as pancreatic beta cells, anterior pituitary cells and neurons. Consequently, LTCC blockers represent a potential new therapy to reduce the toxic effects of excess iron.

Keywords

Hemochromatosis Iron L-type Ca2+ channels Cardiomyopathy Endocrinopathy Oxidative stress 

Abbreviations

LTCC

L-type calcium channel

ICa

LTCC current

NTBI

Non-transferrin bound iron

CCB

Calcium channel blocker

AV

Atrioventricular

SA

Sinoatrial

VSMCs

Vascular smooth muscle cells

LIP

Labile intracellular iron pool

DMT1

Divalent metal transporter 1

TfR

Transferrin receptor

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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Gavin Y. Oudit
    • 1
    • 2
    • 3
    • 4
  • Maria G. Trivieri
    • 1
    • 2
  • Neelam Khaper
    • 1
  • Peter P. Liu
    • 1
    • 2
  • Peter H. Backx
    • 1
    • 2
    • 3
    • 4
  1. 1.Heart and Stroke/Richard Lewar Centre of ExcellenceUniversity Health Network, University of TorontoOntarioCanada
  2. 2.Departments of Medicine and PhysiologyUniversity Health Network, University of TorontoOntarioCanada
  3. 3.Division of Cardiology and the Division of Cellular and Molecular BiologyUniversity Health Network, University of TorontoOntarioCanada
  4. 4.Heart and Stroke/Richard Lewar Centre of ExcellenceTorontoCanada

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