L-type Ca2+ channels provide a major pathway for iron entry into cardiomyocytes in iron-overload cardiomyopathy.
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.
Oudit
Gavin Y
GY
Heart and Stroke/Richard Lewar Centre of Excellence, Departments of Medicine and Physiology, University of Toronto, Ontario M5S 3E2, Canada.
Sun
Hui
H
Trivieri
Maria G
MG
Koch
Sheryl E
SE
Dawood
Fayez
F
Ackerley
Cameron
C
Yazdanpanah
Mehrdad
M
Wilson
Greg J
GJ
Schwartz
Arnold
A
Liu
Peter P
PP
Backx
Peter H
PH
D017311:Amlodipine / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D009202:Cardiomyopathies / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D015996:Survival Rate; D014700:Verapamil / Q000494:pharmacology / Q000627:therapeutic use
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D017311:Amlodipine; D014700:Verapamil; D007501:Iron