| Cardiac-specific deletion of acetyl CoA carboxylase 2 prevents metabolic remodeling during pressure-overload hypertrophy. | |
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MedLine Citation:
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PMID: 22730442 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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RATIONALE: Decreased fatty acid oxidation (FAO) with increased reliance on glucose are hallmarks of metabolic remodeling that occurs in pathological cardiac hypertrophy and is associated with decreased myocardial energetics and impaired cardiac function. To date, it has not been tested whether prevention of the metabolic switch that occurs during the development of cardiac hypertrophy has unequivocal benefits on cardiac function and energetics. OBJECTIVE: Because malonyl CoA production via acetyl CoA carboxylase 2 (ACC2) inhibits the entry of long chain fatty acids into the mitochondria, we hypothesized that mice with a cardiac-specific deletion of ACC2 (ACC2H-/-) would maintain cardiac FAO and improve function and energetics during the development of pressure-overload hypertrophy. METHODS AND RESULTS: ACC2 deletion led to a significant reduction in cardiac malonyl CoA levels. In isolated perfused heart experiments, left ventricular function and oxygen consumption were similar in ACC2H-/- mice despite an ≈60% increase in FAO compared with controls (CON). After 8 weeks of pressure overload via transverse aortic constriction (TAC), ACC2H-/- mice exhibited a substrate utilization profile similar to sham animals, whereas CON-TAC hearts had decreased FAO with increased glycolysis and anaplerosis. Myocardial energetics, assessed by 31P nuclear magnetic resonance spectroscopy, and cardiac function were maintained in ACC2H-/- after 8 weeks of TAC. Furthermore, ACC2H-/--TAC demonstrated an attenuation of cardiac hypertrophy with a significant reduction in fibrosis relative to CON-TAC. CONCLUSIONS: These data suggest that reversion to the fetal metabolic profile in chronic pathological hypertrophy is associated with impaired myocardial function and energetics and maintenance of the inherent cardiac metabolic profile and mitochondrial oxidative capacity is a viable therapeutic strategy. |
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Authors:
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Stephen C Kolwicz; David P Olson; Luke C Marney; Lorena Garcia-Menendez; Robert E Synovec; Rong Tian |
Publication Detail:
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Type: In Vitro; Journal Article; Research Support, N.I.H., Extramural Date: 2012-06-22 |
Journal Detail:
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Title: Circulation research Volume: 111 ISSN: 1524-4571 ISO Abbreviation: Circ. Res. Publication Date: 2012 Aug |
Date Detail:
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Created Date: 2012-08-31 Completed Date: 2012-11-30 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 0047103 Medline TA: Circ Res Country: United States |
Other Details:
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Languages: eng Pagination: 728-38 Citation Subset: IM |
Affiliation:
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Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, 850 Republican St, Seattle, WA 98109, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acetyl-CoA Carboxylase
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genetics,
metabolism* Animals Aorta / pathology Blotting, Western Cardiomegaly / genetics, metabolism* Carnitine / analogs & derivatives, metabolism Constriction, Pathologic Fatty Acids / metabolism Female Fibrosis Heart / physiopathology Male Malonyl Coenzyme A / metabolism Mice Mice, 129 Strain Mice, Inbred C57BL Mice, Knockout Mitochondria, Heart / metabolism Myocardium / enzymology*, metabolism, pathology Oxidation-Reduction Pressure Ventricular Remodeling* |
| Grant Support | |
ID/Acronym/Agency:
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HL059246/HL/NHLBI NIH HHS; HL067970/HL/NHLBI NIH HHS; HL096284/HL/NHLBI NIH HHS; R01 HL059246/HL/NHLBI NIH HHS; R01 HL067970/HL/NHLBI NIH HHS; R01 HL088634/HL/NHLBI NIH HHS; R01 HL110349/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Fatty Acids; 0/acylcarnitine; 524-14-1/Malonyl Coenzyme A; 541-15-1/Carnitine; EC 6.4.1.2/Acacb protein, mouse; EC 6.4.1.2/Acetyl-CoA Carboxylase |
| Comments/Corrections | |
Comment In:
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Circ Res. 2012 Aug 31;111(6):666-8
[PMID:
22935530
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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