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L-type Ca2+ channels provide a major pathway for iron entry into cardiomyocytes in iron-overload cardiomyopathy

Nature Medicine volume 9, pages 1187–1194 (2003)Cite this article

Abstract

Under conditions of iron overload, which are now reaching epidemic proportions worldwide, iron-overload cardiomyopathy is the most important prognostic factor in patient survival. We hypothesize that in iron-overload disorders, iron accumulation in the heart depends on ferrous iron (Fe2+) permeation through the L-type voltage-dependent Ca2+ channel (LVDCC), a promiscuous divalent cation transporter. Iron overload in mice was associated with increased mortality, systolic and diastolic dysfunction, bradycardia, hypotension, increased myocardial fibrosis and elevated oxidative stress. Treatment with LVDCC blockers (CCBs; amlodipine and verapamil) at therapeutic levels inhibited the LVDCC current in cardiomyocytes, attenuated myocardial iron accumulation and oxidative stress, improved survival, prevented hypotension and preserved heart structure and function. Consistent with the role of LVDCCs in myocardial iron uptake, iron-overloaded transgenic mice with cardiac-specific overexpression of the LVDCC α1-subunit had twofold higher myocardial iron and oxidative stress levels, as well as greater impairment in cardiac function, compared with littermate controls; LVDCC blockade was again protective. Our results indicate that cardiac LVDCCs are key transporters of iron into cardiomyocytes under iron-overloaded conditions, and potentially represent a new therapeutic target to reduce the cardiovascular burden from iron overload.

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Figure 1: Survival analysis and echocardiographic assessment of cardiac systolic and diastolic function in iron-injected mice.
Figure 2: Histological characterization of the myocardium in iron-injected mice.
Figure 3: Myocardial and hepatic iron levels and oxidative stress in mice injected with iron for 4 weeks.
Figure 4: Effects of verapamil and iron overload on LVDCC current in ventricular myocytes.

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Acknowledgements

We acknowledge the financial support from the Canadian Institute for Health Research (P.H.B. and P.L.); Heart and Stroke Foundation of Ontario (P.H.B. and P.L. and the US National Institutes of Health (P01 HL22619 to A.S.; NIH Training Grant T32 HL07382 to A.S. and S.E.K.) G.Y.O. is a recipient of a Postdoctoral Fellowship from the Canadian Institute for Health Research and the Heart and Stroke Foundation of Canada, and P.H.B. is a Career Investigator of the Heart and Stroke Foundation of Ontario. Technical assistance from P. Wilson and S. Omar is gratefully acknowledged. We thank Pfizer Inc. for measuring plasma amlodipine levels. This work was presented as an abstract at the American Heart Association Meetings in Anaheim, California, 2001 and Chicago, Illinois, 2002.

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Authors and Affiliations

  1. Departments of Medicine and Physiology, Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, M5S 3E2, Ontario, Canada

    Gavin Y Oudit, Hui Sun, Maria G Trivieri, Fayez Dawood, Mehrdad Yazdanpanah, Peter P Liu & Peter H Backx

  2. Department of Pathology, Hospital for Sick Children, Toronto, M5G 1X8, Ontario, Canada

    Cameron Ackerley & Greg J Wilson

  3. Institute of Molecular Pharmacology and Biophysics, CVRC University of Cincinnati Medical Center, Cincinnati, 45267-0828, Ohio, USA

    Sheryl E Koch & Arnold Schwartz

  4. Division of Cardiology, University Health Network, Toronto, M5G 2C4, Ontario, Canada

    Gavin Y Oudit, Peter P Liu & Peter H Backx

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Oudit, G., Sun, H., Trivieri, M. et al. L-type Ca2+ channels provide a major pathway for iron entry into cardiomyocytes in iron-overload cardiomyopathy. Nat Med 9, 1187–1194 (2003). https://doi.org/10.1038/nm920

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