Related Experiment Video
Updated: Jun 5, 2026
Quantitating Iron Transport Across the Mouse Placenta In Vivo Using Nonradioactive Iron Isotopes
Published on: May 10, 2022
Interdependence of cardiac iron and calcium in a murine model of iron overload
Maya Otto-Duessel1, Casey Brewer, John C Wood
1Division of Pediatric Cardiology, Department of Cardiology, Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA.
Insights
Vitamin D deficiency increases liver iron but not cardiac iron in mice. However, cardiac iron uptake is linked to cardiac calcium levels and can be reduced by verapamil, suggesting a calcium-iron relationship.
Area of Science:
- Cardiovascular Medicine
- Endocrinology
- Hematology
Background:
- Iron cardiomyopathy in beta-thalassemia major is linked to vitamin D deficiency.
- The ratio of 25-OH-D3 to 1,25-(OH)2-D3, a parathyroid hormone (PTH) surrogate, predicts cardiac iron.
- Increased PTH and 1,25-(OH)2-D3 may up-regulate L-type voltage-gated calcium channels (LVGCC), the proposed cardiac iron uptake pathway.
Purpose of the Study:
- To investigate the role of vitamin D deficiency in cardiac iron accumulation.
- To determine if vitamin D deficiency alters LVGCC regulation and impacts cardiac iron uptake.
- To explore the relationship between cardiac calcium, iron, and LVGCC activity.
Main Methods:
- Hemojuvelin knockout mice were subjected to vitamin D depletion, calcitriol, or PTH treatment.
- Mice received either verapamil (a Ca(2+)-channel blocker) or saline.
- Cardiac and hepatic iron, calcium, and manganese levels were measured; LVGCC activity was assessed via Mn(2+) infusion.
Main Results:
- Vitamin D depletion increased liver iron but did not affect cardiac iron levels.
- Cardiac iron levels were proportional to cardiac calcium content (r(2) = 0.6; P < 0.0001).
- Verapamil treatment significantly reduced cardiac (34%) and hepatic (28%) iron levels, maintaining the cardiac iron-calcium association.
Conclusions:
- Vitamin D deficiency is associated with increased liver iron, not cardiac iron, in this model.
- Cardiac iron uptake is strongly correlated with cardiac calcium levels.
- Blocking calcium channels with verapamil attenuates cardiac iron accumulation, suggesting a link between calcium and iron transport.
Abstract:
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.
