| Heme levels are increased in human failing hearts. | |
MedLine Citation:
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PMID: 23500306 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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OBJECTIVES: The goal of this study was to characterize the regulation of heme and non-heme iron in human failing hearts. BACKGROUND: Iron is an essential molecule for cellular physiology, but in excess it facilitates oxidative stress. Mitochondria are the key regulators of iron homeostasis through heme and iron-sulfur cluster synthesis. Because mitochondrial function is depressed in failing hearts and iron accumulation can lead to oxidative stress, we hypothesized that iron regulation may also be impaired in heart failure (HF). METHODS: We measured mitochondrial and cytosolic heme and non-heme iron levels in failing human hearts retrieved during cardiac transplantation surgery. In addition, we examined the expression of genes regulating cellular iron homeostasis, the heme biosynthetic pathway, and micro-RNAs that may potentially target iron regulatory networks. RESULTS: Although cytosolic non-heme iron levels were reduced in HF, mitochondrial iron content was maintained. Moreover, we observed a significant increase in heme levels in failing hearts, with corresponding feedback inhibition of the heme synthetic enzymes and no change in heme degradation. The rate-limiting enzyme in heme synthesis, delta-aminolevulinic acid synthase 2 (ALAS2), was significantly upregulated in HF. Overexpression of ALAS2 in H9c2 cardiac myoblasts resulted in increased heme levels, and hypoxia and erythropoietin treatment increased heme production through upregulation of ALAS2. Finally, increased heme levels in cardiac myoblasts were associated with excess production of reactive oxygen species and cell death, suggesting a maladaptive role for increased heme in HF. CONCLUSIONS: Despite global mitochondrial dysfunction, heme levels are maintained above baseline in human failing hearts. |
Authors:
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Arineh Khechaduri; Marina Bayeva; Hsiang-Chun Chang; Hossein Ardehali |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, N.I.H., Extramural Date: 2013-03-06 |
Journal Detail:
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Title: Journal of the American College of Cardiology Volume: 61 ISSN: 1558-3597 ISO Abbreviation: J. Am. Coll. Cardiol. Publication Date: 2013 May |
Date Detail:
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Created Date: 2013-05-03 Completed Date: 2013-06-25 Revised Date: 2014-05-08 |
Medline Journal Info:
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Nlm Unique ID: 8301365 Medline TA: J Am Coll Cardiol Country: United States |
Other Details:
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Languages: eng Pagination: 1884-93 Citation Subset: AIM; IM |
Copyright Information:
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Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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5-Aminolevulinate Synthetase
/
biosynthesis,
genetics Apoptosis Blotting, Western Cells, Cultured Cytosol / metabolism, pathology Gene Expression Regulation Heart Failure / metabolism*, pathology Heme / biosynthesis* Humans Mitochondria, Heart / genetics, metabolism*, pathology Myocytes, Cardiac / metabolism*, pathology RNA / genetics Reactive Oxygen Species Real-Time Polymerase Chain Reaction |
| Grant Support | |
ID/Acronym/Agency:
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1P01 HL108795/HL/NHLBI NIH HHS; K02 HL107448/HL/NHLBI NIH HHS; K02 HL107448/HL/NHLBI NIH HHS; R01 HL087149/HL/NHLBI NIH HHS; R01 HL104181/HL/NHLBI NIH HHS; R01 HL104181/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Reactive Oxygen Species; 42VZT0U6YR/Heme; 63231-63-0/RNA; EC 2.3.1.37/5-Aminolevulinate Synthetase; EC 2.3.1.37/ALAS2 protein, human |
| Comments/Corrections | |
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