Interdependence of cardiac iron and calcium in a murine model of iron overload.
Iron cardiomyopathy in ß-thalassemia major patients is associated with a vitamin D deficiency. Stores of 25-OH-D3 are markedly reduced, whereas the active metabolite, 1-25-(OH)-D3, is normal or increased. Interestingly, the ratio of 25-OH-D3 to 1-25-(OH)-D3 (a surrogate for parathyroid hormone [PTH]) is the strongest predictor of cardiac iron. Increased PTH and 1-25-OH-D3 levels have been shown to up-regulate L-type voltage-gated calcium channels (LVGCC), the putative channel for cardiac iron uptake. Therefore, we postulate that a vitamin D deficiency increases cardiac iron by altering LVGCC regulation. Hemojuvelin knockout mice were calcitriol treated, PTH treated, vitamin D-depleted, or untreated. Half of the animals in each group received the Ca(2+)-channel blocker verapamil. Mn(2+) was infused to determine LVGCC activity. Hearts and livers were harvested for iron, calcium, and manganese measurements as well as histology. Cardiac iron did not differ among the treatment groups; however, liver iron was increased in vitamin D-depleted animals (P < 0.0003). Cardiac iron levels did not correlate with manganese uptake but were proportional to cardiac calcium levels (r(2) = 0.6; P < 0.0001). Verapamil treatment reduced both cardiac (P < 0.02) and hepatic (P < 0.003) iron levels significantly by 34% and 28%, respectively. The association between cardiac iron and calcium levels was maintained after verapamil treatment (r(2) = 0.3; P < 0.008). Vitamin D depletion is associated with an increase in liver, but not cardiac, iron accumulation. Cardiac iron uptake was strongly correlated with cardiac calcium stores and was significantly attenuated by verapamil, suggesting that cardiac calcium and iron are related.
Division of Pediatric Cardiology, Department of Cardiology, Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA.
Maya
M
Otto-Duessel
Casey
C
Brewer
John C
JC
Wood
D000818:Animals; D002117:Calcitriol / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D006309:Hearing / Q000187:drug effects*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload / Q000188:drug therapy; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D014700:Verapamil / Q000494:pharmacology
D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D014700:Verapamil; D007501:Iron; D002117:Calcitriol; D002118:Calcium
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