Medline Abstract

Nat Med 2003;9(9): 1187-94

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

GY Oudit, H Sun, MG Trivieri, SE Koch, F Dawood, C Ackerley, M
Yazdanpanah, GJ Wilson, A Schwartz, PP Liu, and PH Backx

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

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
alpha1-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.

Publication Types:

Journal article

MeSH Terms:

Amlodipine
Animals
Biological Transport
Calcium Channel Blockers
Calcium Channels
Cardiomyopathies
Iron
Iron Overload
Male
Mice
Mice, Inbred Strains
Myocardium
Myocytes, Cardiac
Oxidative Stress
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Survival Rate
Verapamil

PMID: 12937413

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