Document Detail


Cardiac-specific deletion of acetyl CoA carboxylase 2 prevents metabolic remodeling during pressure-overload hypertrophy.
MedLine Citation:
PMID:  22730442     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Stephen C Kolwicz; David P Olson; Luke C Marney; Lorena Garcia-Menendez; Robert E Synovec; Rong Tian
Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural     Date:  2012-06-22
Journal Detail:
Title:  Circulation research     Volume:  111     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-08-31     Completed Date:  2012-11-30     Revised Date:  2013-09-03    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  728-38     Citation Subset:  IM    
Affiliation:
Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, 850 Republican St, Seattle, WA 98109, USA.
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MeSH Terms
Descriptor/Qualifier:
Acetyl-CoA Carboxylase / 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:
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:
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:
Circ Res. 2012 Aug 31;111(6):666-8   [PMID:  22935530 ]

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