| Limited functional and metabolic improvements in hypertrophic and healthy rat heart overexpressing the skeletal muscle isoform of SERCA1 by adenoviral gene transfer in vivo. | |
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MedLine Citation:
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PMID: 18952713 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Adenoviral gene transfer of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a to the hypertrophic heart in vivo has been consistently reported to lead to enhanced myocardial contractility. It is unknown if the faster skeletal muscle isoform, SERCA1, expressed in the whole heart in early failure, leads to similar improvements and whether metabolic requirements are maintained during an adrenergic challenge. In this study, Ad.cmv.SERCA1 was delivered in vivo to aortic banded and sham-operated Sprague-Dawley rat hearts. The total SERCA content increased 34%. At 48-72 h posttransfer, echocardiograms were acquired, hearts were excised and retrograded perfused, and hemodynamics were measured parallel to NMR measures of the phosphocreatine (PCr)-to-ATP ratio (PCr/ATP) and energy substrate selection at basal and high workloads (isoproterenol). In the Langendorff mode, the rate-pressure product was enhanced 27% with SERCA1 in hypertrophic hearts and 10% in shams. The adrenergic response to isoproterenol was significantly potentiated in both groups with SERCA1. 31P NMR analysis of PCr/ATP revealed that the ratio remained low in the hypertrophic group with SERCA1 overexpression and was not further compromised with adrenergic challenge. 13C NMR analysis revealed fat and carbohydrate oxidation were unaffected at basal with SERCA1 expression; however, there was a shift from fats to carbohydrates at higher workloads with SERCA1 in both groups. Transport of NADH-reducing equivalents into the mitochondria via the alpha-ketoglutamate-malate transporter was not affected by either SERCA1 overexpression or adrenergic challenge in both groups. Echocardiograms revealed an important distinction between in vivo versus ex vivo data. In contrast to previous SERCA2a studies, the echocardiogram data revealed that SERCA1 expression compromised function (fractional shortening) in the hypertrophic group. Shams were unaffected. While our ex vivo findings support much of the earlier cardiomyocyte and transgenic data, the in vivo data challenge previous reports of improved cardiac function in heart failure models after SERCA intervention. |
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Authors:
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J Michael O'Donnell; Aaron Fields; Xianyao Xu; Shamim A K Chowdhury; David L Geenen; Jian Bi |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2008-10-24 |
Journal Detail:
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Title: American journal of physiology. Heart and circulatory physiology Volume: 295 ISSN: 0363-6135 ISO Abbreviation: Am. J. Physiol. Heart Circ. Physiol. Publication Date: 2008 Dec |
Date Detail:
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Created Date: 2008-12-05 Completed Date: 2009-01-30 Revised Date: 2010-09-21 |
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: H2483-94 Citation Subset: IM |
Affiliation:
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Department of Physiology and Biophysics M/C 901 College of Medicine, University of Illinois, 835 S. Wolcott Ave., Chicago, IL 60612, USA. odonnell@uic.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenosine Triphosphate
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metabolism Adenoviridae / genetics* Adrenergic beta-Agonists / pharmacology Animals Cardiomegaly / enzymology, genetics, therapy*, ultrasonography Carrier Proteins / metabolism Citric Acid Cycle Disease Models, Animal Energy Metabolism* / drug effects Gene Therapy* Gene Transfer Techniques Genetic Vectors* Hemodynamics Isoproterenol / pharmacology Magnetic Resonance Spectroscopy Male Mitochondria, Heart / metabolism Muscle, Skeletal / enzymology Myocardial Contraction* / drug effects Myocardium / enzymology*, pathology Oxidation-Reduction Palmitic Acid / metabolism Phosphocreatine / metabolism Rats Rats, Sprague-Dawley Sarcoplasmic Reticulum Calcium-Transporting ATPases / genetics, metabolism* Time Factors |
| Grant Support | |
ID/Acronym/Agency:
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HL-079415/HL/NHLBI NIH HHS; HL-62426/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Adrenergic beta-Agonists; 0/Carrier Proteins; 118901-35-2/calsequestrin protein, rat; 56-65-5/Adenosine Triphosphate; 57-10-3/Palmitic Acid; 67-07-2/Phosphocreatine; 7683-59-2/Isoproterenol; EC 3.6.3.8/Atp2a2 protein, rat; EC 3.6.3.8/Sarcoplasmic Reticulum Calcium-Transporting ATPases |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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