| Autor: |
Chung YJ; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom., Luo A; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.; Medical College, Wuhan University of Science and Technology, Wuhan, China., Park KC; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom., Loonat AA; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom., Lakhal-Littleton S; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom., Robbins PA; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom., Swietach P; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom. |
| Abstrakt: |
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. |
