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Iron-deficiency anemia reduces cardiac contraction by downregulating RyR2 channels and suppressing SERCA pump activity
Yu Jin Chung, … , Peter A. Robbins, Pawel Swietach
Yu Jin Chung, … , Peter A. Robbins, Pawel Swietach
Published February 19, 2019
Citation Information: JCI Insight. 2019;4(7):e125618. https://doi.org/10.1172/jci.insight.125618.
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Research Article Cardiology

Iron-deficiency anemia reduces cardiac contraction by downregulating RyR2 channels and suppressing SERCA pump activity

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Abstract

Iron deficiency is present in ~50% of heart failure (HF) patients. Large multicenter trials have shown that treatment of iron deficiency with i.v. iron benefits HF patients, but the underlying mechanisms are not known. To investigate the actions of iron deficiency on the heart, mice were fed an iron-depleted diet, and some received i.v. ferric carboxymaltose (FCM), an iron supplementation used clinically. Iron-deficient animals became anemic and had reduced ventricular ejection fraction measured by magnetic resonance imaging. Ca2+ signaling, a pathway linked to the contractile deficit in failing hearts, was also significantly affected. Ventricular myocytes isolated from iron-deficient animals produced smaller Ca2+ transients from an elevated diastolic baseline but had unchanged sarcoplasmic reticulum (SR) Ca2+ load, trigger L-type Ca2+ current, or cytoplasmic Ca2+ buffering. Reduced fractional release from the SR was due to downregulated RyR2 channels, detected at protein and message levels. The constancy of diastolic SR Ca2+ load is explained by reduced RyR2 permeability in combination with right-shifted SERCA activity due to dephosphorylation of its regulator phospholamban. Supplementing iron levels with FCM restored normal Ca2+ signaling and ejection fraction. Thus, 2 Ca2+-handling proteins previously implicated in HF become functionally impaired in iron-deficiency anemia, but their activity is rescued by i.v. iron supplementation.

Authors

Yu Jin Chung, Antao Luo, Kyung Chan Park, Aminah A. Loonat, Samira Lakhal-Littleton, Peter A. Robbins, Pawel Swietach

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Figure 1

Characterizing the murine model of iron deficiency.

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Characterizing the murine model of iron deficiency.
(A) Timeline of the ...
(A) Timeline of the experimental protocol for establishing dietary iron deficiency in 3-week-old mice, showing time points at which either FCM or saline is injected, MRI scanning is performed, and hearts are excised for further studies. (B) Body mass and (C) tail vein blood hemoglobin concentration were measured during the 5-week dietary intervention (n = 6 animals/group). (D) Ferritin, iron, transferrin, and transferrin saturation (TSat) measured in the serum after 5 weeks of diet. n > 10 animals/group. (E) Elemental iron content in lysates of the liver, spleen, and heart, normalized to wet tissue weight, after 5 weeks of diet. n > 10 animals/group. (F) Cardiac ferritin expression measured by ELISA after 5 weeks of diet (n > 7 animals/group). (G) Immunoblot for HIF1α and HIF2α in cardiac lysates, normalized to histone H3 as the loading control, after 5 weeks of diet (n = 3 animals/group). (H) RT-qPCR analysis of mRNA levels of the HIF target genes Eno1 and Glut1 and non-HIF target gene Glut4 after 5 weeks of diet. n = 9 animals/group. (I) Immunoblot for the histone marks H3K36, -K9, and -K4 after 5 weeks of diet (n = 3 animals/group). See Supplemental Table 1 for details of the number of experimental repeats. Note that HIF1α in G and H3K36me3 in I were blotted from the same membrane and, therefore, have the same nuclear loading control (histone H3). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. P values determined by 2-way ANOVA for A and B; 1-way ANOVA for D and E; unpaired Student’s t test (2-tailed) for F and H.

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