| Calcineurin-induced energy wasting in a transgenic mouse model of heart failure. | |
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MedLine Citation:
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PMID: 18192216 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Overexpression of calcineurin (CLN) in the mouse heart induces severe hypertrophy that progresses to heart failure, providing an opportunity to define the relationship between energetics and contractile performance in the severely failing mouse heart. Contractile performance was studied in isolated hearts at different pacing frequencies and during dobutamine challenge. Energetics were assessed by 31P-NMR spectroscopy as ATP and phosphocreatine concentrations ([ATP] and [PCr]) and free energy of ATP hydrolysis (|Delta G( approximately ATP)|). Mitochondrial and glycolytic enzyme activities, myocardial O2 consumption, and myocyte ultrastructure were determined. In transgenic (TG) hearts at all levels of work, indexes of systolic performance were reduced and [ATP] and capacity for ATP synthesis were lower than in non-TG hearts. This is the first report showing that myocardial [ATP] is lower in a TG mouse model of heart failure. [PCr] was also lower, despite an unexpected increase in the total creatine pool. Because Pi concentration remained low, despite lower [ATP] and [PCr], |Delta G( approximately ATP)| was normal; however, chemical energy did not translate to systolic performance. This was most apparent with beta-adrenergic stimulation of TG hearts, during which, for similar changes in |Delta G( approximately ATP)|, systolic pressure decreased, rather than increased. Structural abnormalities observed for sarcomeres and mitochondria likely contribute to decreased contractile performance. On the basis of the increases in enzyme activities of proteins important for ATP supply observed after treatment with the CLN inhibitor cyclosporin A, we also conclude that CLN directed inhibition of ATP-producing pathways in non-TG and TG hearts. |
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Authors:
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Ilka Pinz; Sanford E Ostroy; Kirsten Hoyer; Hanna Osinska; Jeffrey Robbins; Jeffery D Molkentin; Joanne S Ingwall |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, N.I.H., Extramural Date: 2008-01-11 |
Journal Detail:
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Title: American journal of physiology. Heart and circulatory physiology Volume: 294 ISSN: 0363-6135 ISO Abbreviation: Am. J. Physiol. Heart Circ. Physiol. Publication Date: 2008 Mar |
Date Detail:
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Created Date: 2008-03-07 Completed Date: 2008-05-15 Revised Date: 2008-11-21 |
Medline Journal Info:
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Nlm Unique ID: 100901228 Medline TA: Am J Physiol Heart Circ Physiol Country: United States |
Other Details:
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Languages: eng Pagination: H1459-66 Citation Subset: IM |
Affiliation:
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NMR Laboratory for Physiological Chemistry, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adenosine Diphosphate
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metabolism Adenosine Monophosphate / metabolism Adenosine Triphosphate / metabolism Animals Calcineurin / pharmacology* Creatine / metabolism Energy Metabolism / drug effects* Heart Failure / genetics, metabolism* Magnetic Resonance Spectroscopy Mice Mice, Transgenic Microscopy, Electron Myocytes, Cardiac / drug effects, ultrastructure Oxygen Consumption / drug effects Phosphocreatine / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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HL-075619/HL/NHLBI NIH HHS; HL-52320/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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56-65-5/Adenosine Triphosphate; 57-00-1/Creatine; 58-64-0/Adenosine Diphosphate; 61-19-8/Adenosine Monophosphate; 67-07-2/Phosphocreatine; EC 3.1.3.16/Calcineurin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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